UA120856C2 - Methods and compositions for treating hiv-related disorders - Google Patents

Abstract

Certain adjunctive therapies comprising a kynurenine-3-monooxygenase inhibitor and an antiviral agent for treating HIV-related disorders are provided herein. These disorders include AIDS dementia complex, AIDS-induced encephalopathy, НIV-associated neurocognitive disorder, asymptomatic neurocognitive impairment, minor neurocognitive disorder, minor cognitive motor disorder, vacuolar myelopathy, peripheral neuropathies, and polymyositis. Also provided are pharmaceutical compositions comprising a kynurenine-3-monooxygenase inhibitor and an antiviral agent.

Description

This application claims priority from prior application US Mo. 62/025,840, filed Jul. 17, 2014, which is incorporated herein by reference in its entirety.

This application provides certain options for adjunctive therapy for HIV-related disorders, and said options include administration of a kynurenine-3-monooxygenase inhibitor along with an antiviral agent. This application also proposes pharmaceutical compositions containing kynurenine-3-monooxygenase inhibitor and an antiviral agent.

Inflammatory processes contribute significantly to the progression and manifestation of a wide range of central nervous system (CNS) diseases, including acute and chronic microbial infections, autoimmune processes, stroke, and physical CNS trauma. There are multiple mechanisms by which inflammation can cause neurological disease, including the production of neurotoxic agents by the host or by exogenous microorganisms.

Identifying such mediators and processes that cause the production and accumulation of neurotoxic agents is an important stage in the development of rational approaches to therapy. Movement abnormalities, cognitive impairment, and dementia (encephalopathy) are common complications of human immunodeficiency virus (HIV) infection that may occur independently of opportunistic CNS infections. Neurological symptoms most often underlie HIV encephalitis, an inflammatory condition characterized by the presence of HIV-infected macrophages, astrogliosis, white matter in the brain, and neuronal damage (loss of neurons and synapses). It has been hypothesized that toxin production by microglia/macrophages is a possible mechanism responsible for neurological dysfunction and neurodegeneration because HIV is localized predominantly in microglia/macrophages and because macrophage-tropic isolates are associated with neurological disease to a greater extent than T-cell- tropical isolates.

Potential host-encoded neurotoxins include the MMOA receptor agonist quinolinic acid (OSHIMI).

OSHIM is an excitotoxic metabolite of the tryptophan-kynurenine pathway. In models of inflammatory neurological disorders, such as experimental allergic encephalitis, bacterial and viral infections, global forebrain ischemia, or spinal cord injury, the levels of OSIM in the brain are remarkably increased. This increased concentration of OSHIM in the brain may be due to an increased circulating concentration

From excitotoxin or increased synthesis of de Pomo in activated microglia or in macrophages after infiltration. OSHIM is an agonist of a subgroup of MMOA receptors, and when directly injected into the brain region, OSHIM destroys most of the neuronal cell bodies, while not damaging the fibers and terminals of neurons. OSHIM is a relatively weak agonist of the MMOA-receptor complex containing MK2C or MAK20O subunits, which interacts with greater affinity with the MEK2A subunit (7-10 μmol) and the MK2B subunit (100 μmol).

The neurotoxic effects of this compound were studied on various model systems of the mouse brain, and different results were obtained: chronic exposure to organotypic cortico-striatal cultures of a submicromolar concentration of OSHIM caused histological signs of pathology; similar results were obtained after chronic exposure to cultured neurons.

A significant increase in OSHIM concentrations is observed in the cerebrospinal fluid (CSF) and blood of HIV-infected patients and simian immunodeficiency virus (SIM)-infected macaques, and begins shortly after primary infection. Increased levels of OSIM in CMP are associated with motor defects and virus release from the CNS in the early asymptomatic stages of the disease and are correlated with quantitative indicators of neuropsychological defects, striatal and limbic atrophy and markers of intrathecal immune activation (concentrations in CMP of VD2-microglobulin and neopterin) in patients , which are at a late stage. One study reported that in HIV-infected patients, concentrations of OSHIM in the brain were increased 300-fold to concentrations that were 8.9-fold higher than those in the cerebrospinal fluid (CSF). Moreover, in retrovirus-infected macaques, the largest brain kynurenine pathway responses and CMP were associated with retrovirus-induced encephalitis.

Direct measurements of the amount of OSHIM in the brain of macaques with encephalitis, carried out in blood, demonstrated that almost all OSHIM (98 9o) was synthesized locally in the brain.

In contrast to changes in the brain, there was no difference in any systemic measure when comparing macaques with and without encephalitis. These results demonstrate the role of induction of indoleamine-2,3-dioxygenase (00) in the acceleration of the local formation of OSI in the brain tissue, in particular, in areas of encephalitis, than the entry of OSI into the brain from the meninges or blood. In fact, significant increases in the activities of IBO and two other enzymes of the kynurenine pathway of tryptophan metabolism, kynurenine-3-monooxygenase (KMO) and bo-kynureninase (KUM), were found in areas of brain inflammation. Accordingly, strategies to reduce OSHM production, targeting intracerebral regions, represent potential approaches for therapy.

The pathogenesis of human and simian immunodeficiency virus is characterized by depletion of CO4(tyu) T-cells and chronic activation of T-cells, which ultimately leads to the development

AIDS. СО4(k) T-helper (T(x)) cells provide protective immunity and immune regulation through various functional subsets of immune cells, including TO)1, T092, T-regulatory (Tbreg)) and interleukin-17 (IL-17 )-secreting T(x)17 cells. Because IL-17 can enhance the body's defense mechanisms against microbial agents, thereby maintaining the integrity of the mucosal barrier, the loss of T(x)17 cells can contribute to the movement of microorganisms and persistent inflammation. It was found that in HIV-seropositive subjects, the progression of the disease is associated with the loss of T(x)17 cells and a reciprocal increase in the fraction of immunosuppressive T(reg) cells in peripheral blood and in biopsy samples from the rectosigmoid region. Loss of TCO)17/T(reg) balance is associated with induction of indoleamine-2,3-dioxygenase 1 (IBOY1) by myeloid antigen-presenting dendritic cells and with increased concentration of microbial products in plasma. The loss of the balance of T(O)17/T(reg) and myo is directly mediated by the proximal catabolite of tryptophan from the metabolism of /O, 3-oxyanthrinilic acid (3-OH-AA). It has been suggested that the induction of IU may represent a critical initiating event that leads to a change in T0)17/(reg) balance and subsequent maintenance of a chronic inflammatory state in progressive HIV disease.

Accordingly, strategies to reduce 3-OH-AA levels are predicted to ameliorate or alleviate systemic inflammation after HIV infection.

KMO catalyzes the conversion of kynurenine (KUM) into 3-hydroxykynurenine (3-NK or 3-OH-KUM), which is then cleaved by KUM to 3-oxyanthrinilic acid, and then to OSHIM. 3-YUN-KUM and OSHIM act synergistically, that is, 3-OH-KUM significantly potentiates the excitotoxic effect of OSHIM.

Studies carried out in several laboratories have provided evidence that a shift in the metabolism of the KUM pathway from branching 3-OH-KUM/OSHIM to increasing the formation of neuroprotective KUMA (kynurenic acid) in the brain leads to neuroprotection.

In addition to effects in the brain, CMO inhibition is also thought to affect peripheral tissues. Based on the role of 3-OH-AA in modulating T(x)17 cells and IL-17LL-23 balance in HIV pathogenesis, CMO inhibitors have been suggested to prevent increased

On the movement of microorganisms through the mucous membrane of the gastrointestinal tract and systemic inflammation in patients with long-term progressive disease. Thus, inhibition

CMO may be useful in the treatment of peripheral disorders associated with HIV, as well as brain diseases.

Compounds and pharmaceutically acceptable salts of the compounds described in this application that inhibit

CMOs disclosed in PCT patent publications UM/O2013/033068 and MUMO2013/033085, each of which is fully incorporated into this application by reference.

There remains a need for methods and compositions that are effective in the adjunctive treatment of disorders associated with HIV infection.

Accordingly, the present application provides a method of treating an HIV-related disorder in a subject infected with HIV, said method comprising additionally administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: xx

IOM

- he is at 2 o'clock

The formula or a pharmaceutically acceptable salt of the specified compound; and the specified subject is also administered an antiviral agent; and also:

A" and K? each independently selected from C1-C4 alkoxy group, optionally substituted by one

C3-C6 cycloalkyl substituent, C1-C6 alkyl substituted with one substituent selected from

C1-Cx alkoxy group and C3-Ce cycloalkoxy group, C3-Ce cycloalkoxy group and halogen.

Also proposed is a composition containing an antiviral agent and a compound of Formula I:

MM

- he in o in:

A formula or a pharmaceutically acceptable salt of the specified compound; moreover:

AB and K? each independently selected from a C-C4 alkoxy group, optionally substituted by one

C3-C6 cycloalkyl substituent, C1-C6 alkyl substituted with one substituent selected from

C1-Cx alkoxy group and C3-Ce cycloalkoxy group, C3-Ce cycloalkoxy group and halogen.

Brief description of the drawings

In fig. 1. a dose-dependent increase in the level of kynurenine (KUM) in the extracellular space of the striatum after the introduction of Compound 6 is presented.

In Fig. 2. a dose-dependent increase in the level of kynurenic acid (KUMA) in the extracellular space of the striatum after the introduction of Compound 6 is presented.

In Fig. 3. a dose-dependent increase in the level of anthranilic acid (AA) in the extracellular space of the striatum after the introduction of Compound 6 is presented.

In Fig. 4. insufficient modulation of 3-hydroxykynurenine (3-NK or 3-OH-KUM) in the extracellular space of the striatum after the introduction of Compound 6 is presented.

In Fig. 5. a dose-dependent increase in the level of metabolites of the kynurenine pathway (SK) in the striatum after administration of Compound 6 in wild-type mice is presented.

In Fig. 6. a dose-dependent increase in the level of metabolites of the kynurenine pathway in the striatum after the introduction of Compound 6 in homozygous 2175 CI mice is presented.

In Fig. 7. Modulation of the level of KUM in the striatum after the introduction of Compound 6, KUM and (Compound 6-KUM) is presented.

In Fig. 8. the modulation of the KUMA level in the striatum after the introduction of Compound 6 is presented,

KUM and (Compounds 6-KUM).

In Fig. 9. presented modulation of the level of anthranilic acid (AA) in the striatum after the introduction of Compound 6, KUM and (Compound b-KUM).

In Fig. 10. Modulation of the level of 3-OH-KUM in the striatum after the introduction of Compound 6, KUM and (Compound 6-KUM) is presented.

ИО23| In Fig. 11. Modulation of the level of quinolinic acid (OA) in the striatum after

From the introduction of Compound 6, KUM and (Compound 6-KUM).

In this specification, the following words, phrases and symbols generally have the following meanings, unless the context in which the said words, phrases and symbols are used dictates otherwise. The following abbreviations and terms have the meanings indicated in this application:

A hyphen ("-") not located between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -SOMNaI2 is attached with the help of a carbon atom.

"Alkoxy" means an alkyl group consisting of the specified number of carbon atoms attached by an oxygen bridge, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2 -pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy group, etc. "Cycloalkyl" means a cycloalkyl group, as defined in this application, which is similarly attached via an oxygen bridge.

The term "alkyl" encompasses straight and branched chain containing the specified number of carbon atoms, usually from 1 to 20 carbon atoms, for example from 1 to 8 carbon atoms, for example from 1 to b carbon atoms. For example, C1-C6 alkyl includes straight and branched alkyl chains consisting of 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like. When an alkyl residue containing a specific number of carbons is specified, then the specified residue is intended to include all geometric isomers containing the given number of carbons; thus, for example, "butyl" is intended to include n-butyl, t-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl.

The term "cycloalkyl" means a saturated hydrocarbon ring group containing a specified number of carbon atoms, usually from 3 to 7 ring carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, as well as bridging and framework saturated ring groups such as norbornene.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The terms "optional" or "optional" mean that the event or circumstance described below may or may not occur, and that the description includes cases in which the given event or condition has occurred and cases in which the given event or the circumstance did not arise. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined below.

With respect to any group containing one or more substituents, such groups, as understood by those skilled in the art, are not intended to introduce any substituent or groups of substituents that are sterically unfavorable, synthetically impractical, and/or or unstable in nature.

The term "substituted" as used herein means that any one or more hydrogens on a specified atom or group are replaced by a selected variant from the specified group, provided that the normal valency of the specified atom is not exceeded. When the substituent is oxo (ie -0), 2 hydrogens are substituted on the atom. Combinations of substituents and/or variables are permissible only if such combinations result in a stable compound or suitable synthetic intermediates. A stable compound or stable structure means a compound that is sufficiently stable to withstand isolation from a reaction mixture and subsequent formulation into a formulation having at least practical utility. Unless otherwise stated, substituents are named in the central structure. For example, it should be understood that when (cycloalkylalkyl) is listed as a possible substituent, the point of attachment of this substituent to the central structure is located in the alkyl part.

The compounds described in this application include, but are not limited to, optical isomers, racemates, and other mixtures of said compounds. In such situations, individual enantiomers or diastereomers, i.e. optically active forms, can be obtained by asymmetric synthesis or by resolution of racemates. Resolution of the racemates can be carried out, for example, by conventional methods, such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral high-performance liquid chromatography (HPLC) column. The term "isomers" means different compounds which

Zo are characterized by the same molecular formula. The term "stereoisomers" refers to isomers that differ only in the way the atoms are arranged in space. The term "enantiomers" refers to stereoisomers that are non-overlapping mirror images of one another. A 1:11 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(w)" may be used to denote a racemic mixture in appropriate cases. The term "diastereoisomers" means stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of each other. The term "meso compound" or "mesoisomer" means an optically inactive member of the series of stereoisomers. Mesoisomers contain two or more stereocenters, but are not chiral (that is, the molecule has a plane of symmetry). The absolute stereochemistry is indicated according to the K-5 system

Kana - Ingolda - Preloga. If the compound is a pure enantiomer, the stereochemistry at each chiral carbon may be indicated as K or 5. Separated compounds whose absolute configuration is unknown may be indicated as (w) or (-) depending on the direction (dextrorotatory or levorotatory), in to which these compounds rotate the plane of polarizing light at the wavelength of the O line of the sodium spectrum.

When the compounds described in this application exist in different tautomeric forms, the term "compounds" includes all tautomeric forms of the compound. Such compounds also include crystalline forms, including polymorphs and clathrates. Similarly, the term "salt" includes all tautomeric forms and crystalline forms of the compound. The term "tautomers" means structurally different isomers that are mutually converted in the process of tautomerization. Tautomerization is a form of isomerization and includes prototropic tautomerization or proton transfer tautomerization, which is considered a subset of acid-base chemistry. Prototropic tautomerization or proton transfer tautomerization involves proton migration that is accompanied by changes in bond multiplicity, often with interconversion of a single bond with an adjacent double bond. When tautomerization is possible (for example, in solution), a chemical equilibrium of tautomers can be achieved. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the mutual transformation of tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerization is phenol-ketol tautomerization. A specific example of phenol-ketol tautomerization is the mutual transformation of tautomers of pyridin-4-ol and pyridin-4(1H)-one. for Pharmaceutically acceptable forms of the compounds described in this application include pharmaceutically acceptable salts, prodrugs and mixtures of said forms. According to some embodiments of the present invention, the compounds described in this application are in the form of pharmaceutically acceptable salts and prodrugs. "Pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids such as hydrochloride, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and the like, as well as salts formed with organic acids such as malate , maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate and alkanoate such as acetate, HOOC-(CH2)p-COOH, where n is 0 - 4, and similar salts. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. In addition, if the compounds described in this application are obtained in the form of an acid addition salt, the free base can be obtained by alkalinizing the acid salt solution. conversely, if the product is a free base, the addition salt, in particular, a pharmaceutically acceptable addition salt, can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional methods for preparing acid addition salts from basic compounds. Various synthesis methods are known to those skilled in the art that can be used to obtain non-toxic pharmaceutically acceptable addition salts.

The term "prodrug" means a compound that is administered in an inactive or less active form, which will then be converted (eg, by metabolic processing of the prodrug in the body) into an active compound. The purpose of administration of prodrugs is to optimize the absorption, distribution, metabolism and/or elimination of the drug. Prodrugs can be obtained by deriving an active compound (eg, a compound of Formula I or another compound disclosed and/or described in this application) that will undergo transformation under the conditions of use (eg, in the body) to form an active compound. The conversion of prodrugs to the active compound may occur spontaneously (eg, in a hydrolysis reaction) or may be catalyzed or induced by another agent (eg, enzyme, light, acid or base, and/or temperature). Said agent may be endogenous to the conditions of use (eg, an enzyme present in the cells into which the prodrug is administered, or an acidic environment

From the stomach) or the specified agent can come exogenously. Prodrugs can be obtained by converting one or more functional groups in the active compound to another functional group, which is then converted back to the original functional group upon administration. For example, a hydroxyl functional group can be converted into a sulfonate, phosphate, ester, or carbonate group, which in turn can be hydrolyzed back to a hydroxyl group. Similarly, an amine functional group can be converted to, for example, an amide, carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl functional group, which can be hydrolyzed back to the amino group. A carboxyl functional group can be converted, for example, into an ester (including silyl esters and thioesters), amide, or hydrazide functional group, which can be hydrolyzed back to the carboxyl group. Examples of prodrugs include, but are not limited to, phosphate, acetate, formate, and benzoate derivatives of functional groups (such as alcohol or amine groups) present in the compounds

Formula I and other compounds disclosed and/or described in this application. According to some embodiments of the present invention, "prodrugs" described in this application include any compound that becomes a compound of Formula I! when administered to a patient, for example, after metabolic processing of prodrugs. Examples of prodrugs include derivatives of functional groups such as carboxyl in compounds of Formula I. Examples of carboxyl prodrugs include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. .

Other examples of prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides and ascorbic acid derivatives. Other examples of prodrugs include amides of carboxylic acids. Examples of amide prodrugs include metabolically labile amides formed, for example, from an amine and a carboxylic acid. Examples of amines include MH, primary and secondary amines such as MNEX and MExXCUu where X is hydrogen, (C1-C18)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl- (C1-C4 )-alkyl--, (C6-C14)-aryl, which is an unsubstituted or substituted base (C1-C2)-alkyl, (C1-

C2)-alkoxy group, fluorine or chlorine; heteroaryl, (C6-C14)-aryl-(C1-C4)-alkyl-1 where aryl is unsubstituted or substituted by a (C1-C2)-alkyl, (C1-C2)-alkyl group, fluorine or chlorine; or heteroaryl-(C1-C4)-alkyl-- and in which Ku takes the values indicated for Ex, excluding 60 hydrogen, or where Kx and Ku together with the nitrogen to which they are attached form an optionally substituted from 4- to 7-membered heterocycloalkyl ring, which optionally contains one or two additional heteroatoms selected from nitrogen, oxygen and sulfur. The discussion of prodrugs is given in the instructions of T. Nidispi apa M. 5(hePa, Rgo-dgpyd5 az Mome! Oeeiiimegu Zubivetv5, Moi. 14 "E She A.S.5.

Zutrovisht Begie5, ip Ejaga V. JuRosne, ed., Viohemegvirie Saigtietz ip Ogyd Oevidp, Ategisap

RPpaptaseshisa! Avzosiayop apa Regdatop Rgez5, 1987 and YuOezidp oi Rgodgydv5, ey. N. Vypadaaga,

Eivemieg, 1985.

The compounds described in this application can be enriched isotopic forms, for example, enriched in 2Н, ЗН, 11С, 13С and/or 14С. According to one embodiment of the present invention, the compounds contain at least one deuterium atom. Such deuterated forms can be obtained, for example, by the procedures described in US Pat. Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of the compounds disclosed and/or described herein. Deuterium-substituted compounds can be synthesized by various methods, such as those described in the publications of JuOeap, O., Kesepi

Aduapsez ip She Zupipezib5 apa Arriisayop5 oi Nadioiiiabeiyedi Sotroypavz iTog Ogyd Oivsomegu apa

OemeIortepi, Sit. Rpapt. Oev5., 2000; 6(10); KabraiKa, ah. ei aI., Te Zupipevziv oi Vadioiabeivyd

Sotroypav5 mia Ogdapoteizaiiis Ipientediaie5, Teimaneagop, 1989, 45(21), 6601-21; and Emap", E., zZupipevziv oi gadioiabiied sotroipoavv, U. Nadioapa!. Spet., 1981, 64(1-2), 9-32. "Solvate" means a compound formed by the interaction of a solvent and a compound or a pharmaceutically acceptable salt of the compound. The term "compound" includes solvates of the compounds.

Similarly, the term "salts"? includes solvate salts. Suitable solvates are pharmaceutically acceptable solvates such as hydrates, including monohydrates and hemihydrates. "Chelate" means a compound formed by the coordination of a compound to a metal ion at two (or more) points. The term "compound" includes chelates of the compound. Likewise, the term "salts" includes chelates of salts. "Non-covalent complex" means a compound formed as a result of the interaction of a compound and another molecule, and in said complex, no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also called ionic bonds). Such non-covalent complexes are included in the term "compound".

The term "hydrogen bond" refers to the form of association between an electronegative atom (also known as a hydrogen bond acceptor) and a hydrogen atom attached to a second, relatively electronegative atom (also known as a hydrogen bond donor). Suitable hydrogen bond donors and acceptors are well known in medicinal chemistry (5. S. Ritepieyi apa A. I. MeosiePap, Te

Nudgodep Vopa, Egeetap, Zap Egapsizso, 1960; A. Tauog apa 0. Keppaga, "Nudgodep Vopa

"Hydrogen bond acceptor" means a group containing oxygen or nitrogen, such as oxygen or nitrogen that is 5p2- hybridized, oxygen or oxygen sulfoxide or M-oxide.

The term "hydrogen bond donor" means an oxygen, nitrogen, or heteroaromatic carbon that carries a hydrogen group containing a ring nitrogen or a heteroaryl group containing a ring nitrogen.

In this application, the terms "group", "radical" or "fragment" mean a functional group or fragment of a molecule that can be attached to a bond or another fragment of a molecule.

The term "active agent" means a compound or a pharmaceutically acceptable salt of a compound that has biological activity. According to some embodiments of the present invention, the "active agent" is a compound or a pharmaceutically acceptable salt of a compound characterized by pharmaceutical applicability. For example, the active agent may be an anti-neurodegenerative therapeutic agent or an antiviral therapeutic agent.

The term "therapeutically effective amount" of a compound or a pharmaceutically acceptable salt of a compound described herein means an amount that, when administered to a human or non-human subject, is effective to provide a therapeutic benefit, such as alleviation of symptoms, slowing disease progression or preventing disease, for example, a therapeutically effective amount may be an amount sufficient to reduce disease symptoms in response to inhibition of CMO activity and modulation of kynurenine pathway metabolites (such as kynurenine, kynurenic acid, anthranilic acid, 3-OH-kynurenine , 3-OH-anthranilic acid or quinolinic acid). According to some embodiments of the present invention, a therapeutically effective amount is an amount sufficient to treat the symptoms of an HIV-related disorder. According to some embodiments of the present invention, a therapeutically effective amount is an amount sufficient to reduce symptoms or side effects of an HIV-related disorder. According to some embodiments of the present invention, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt of the compound is an amount sufficient to prevent a significant increase or a significant decrease in the level of neuronal cell death associated with HIV.

According to some embodiments of the present invention, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt of the compound is an amount sufficient to prevent a significant increase or a significant decrease in the level of OSIM associated with HIV-induced neuronal cell death. According to some embodiments of the present invention, a therapeutically effective amount is an amount sufficient to increase the level of KUMA associated with the state of neuronal cells in a patient infected with HIV.

According to some embodiments of the present invention, a therapeutically effective amount is an amount sufficient to increase the anticonvulsant and neuroprotective properties associated with reduced levels of OSHIM and increased levels of KUMA in a patient infected with HIV. According to some embodiments of the present invention, a therapeutically effective amount is an amount sufficient to modulate inflammation in a patient infected with HIV, including, but not limited to, inflammation in the brain, spinal cord, and peripheral nervous system or in the meninges. In the methods described herein for the adjunctive treatment of an HIV-related disorder, a therapeutically effective amount may also be an amount that, when administered to a patient, is sufficient to slow the progression of the manifest HIV-related disorder or to prevent the onset of symptoms of an HIV-related disorder in a patient taking the composition. In some of the methods described herein for the treatment of an HIV-related disorder, a therapeutically effective amount may also be an amount sufficient to reduce the level of detectable HIV-related neuronal cell death. For example, according to some embodiments of the present invention, a therapeutically effective amount is an amount sufficient to significantly reduce the level of HIV-related neuronal death by providing a detectable decrease in the amount of OSHIM and an increase in the amount of kynurenine, KUMA, or anthranilic acid. In addition, an amount is considered a therapeutically effective amount if the amount is substantially characterized by at least one of the above criteria or experimental conditions, regardless of any inconsistent or contradictory result obtained under a different set of criteria or experimental conditions.

The term "inhibition" means a significant reduction in the original activity of a biological activity or process. "Inhibition of CMO activity" means reduction of CMO activity as a direct or indirect response to the presence of at least one compound or a pharmaceutically acceptable salt of a compound described in this application relative to CMO activity in the absence of at least one specified compound or a pharmaceutically acceptable salt of the compound. Decreased activity may be caused by direct interaction of a compound or a pharmaceutically acceptable salt of said compound with CMO or may be caused by an interaction of a compound or a pharmaceutically acceptable salt of a compound described in this application with one or more other factors that, in turn, affect the activity of CMO .

For example, the presence of a compound or a pharmaceutically acceptable salt of a compound can reduce CMO activity by directly binding to CMO, by stimulating (directly or indirectly) another factor to reduce CMO activity, or by reducing (directly or indirectly) the amount of CMO present in a cell or organism.

Inhibition of CMO activity also means the observed inhibition of 3-NK and OSHIM production in a standard assay such as the assays described below. Inhibition of CMO activity also means an observed increase in KUMA production. According to some embodiments of the present invention, a compound or a pharmaceutically acceptable salt of a compound described in this application is characterized by an IC5O value of less than or equal to 1 micromole. According to some variants of the implementation of this invention, the compound or a pharmaceutically acceptable salt of the specified compound is characterized by an IC50O value of less than or equal to 100 micromoles. According to some variants of the implementation of this invention, the compound or a pharmaceutically acceptable salt of the specified compound is characterized by an IC5O value of less than or equal to 10 nanomoles. Inhibition of CMO activity also means activation, redistribution, rearrangement, or gating of one or more different membrane-bound CMO proteins (such as receptors found in mitochondria), or binding sites may undergo redistribution and gating that can trigger signal transduction. CMO activity may also modulate kynurenine availability, which may affect the synthesis or production of OSHIM, KUMA, anthranilic acid, and/or 3-NK. "Disease responsive to inhibition of CMO activity" means a disease in which inhibition of CMO provides a therapeutic benefit, such as alleviation of symptoms, reduction of disease progression, prevention or delay of disease manifestation, prevention or mitigation of inflammatory response, or inhibition of impaired activity, and/ or the death of certain types of cells (such as neurons). "Treatment" means any treatment of a disease in a patient, including: a) prevention of the disease, in other words, ensuring the absence of the development of clinical symptoms of the disease; B) inhibition of disease progression; c) slowing down or stopping the development of clinical symptoms; and/or () weakening the disease, in other words, ensuring the regression of clinical symptoms. "Subject" or "patient" means an animal, such as a mammal, which is or will be the subject of treatment, observation or experimentation. The methods described in this application may be suitable for both human therapy and veterinary use. According to some variants of implementation of this invention, the subject is a mammal; and according to some variants of the implementation of this invention, the subject is a person.

The term "disease" means an abnormal condition of a human or animal organism or one or more parts of said organism, which disrupts normal functioning, as a rule, manifests itself through characteristic signs and symptoms and causes a decrease in the duration or quality of life of a person or animal. In this application, these terms are generally synonymous and are used interchangeably with the terms "disorder" and "condition" (as a medical condition).

The term "additional" administration means administering to a patient or treating a patient with at least one compound or a pharmaceutically acceptable salt of a compound described herein, in addition to an antiviral agent, simultaneously or at certain intervals before, during or after the administration of an antiviral agent to achieve the desired therapeutic effect.

The term "viral load" refers to the concentration of a virus, such as HIV, in the blood.

A proposed composition comprising an antiviral agent and a compound of Formula I:

MM

-d he in o in2

A formula or a pharmaceutically acceptable salt of the specified compound; where:

AB and K? each independently selected from a C1-C4 alkoxy group, optionally substituted by one

C3-C6 cycloalkyl substituent, C1-C6 alkyl substituted with one substituent selected from

C1-Cx alkoxy group and C3-Ce cycloalkoxy group, C3-Ce cycloalkoxy group and halogen.

According to some variants of the implementation of this invention, K1 is a C1-C4 alkoxy group, optionally substituted by one C3-C6 cycloalkyl substituent.

According to some variants of the implementation of this invention, K1 is a C1-C4 alkoxy group.

According to some variants of implementation of this invention, K1 is a sec-butoxy group.

According to some variants of implementation of this invention, K1 is a (K)-second-butoxy group.

According to some variants of implementation of this invention, K1 is a (5)-tert-butoxy group.

According to some variants of implementation of this invention, KI is an isopropoxy group.

According to some variants of the implementation of this invention, K1 is a C1-C4 alkoxy group substituted by one C3-C6 cycloalkyl substituent.

According to some variants of implementation of this invention Ki is a cyclopropylmethoxy group.

According to some variants of the implementation of this invention CI! is C1-C4 alkyl substituted with one substituent selected from C1-C4 alkoxy group and C3-C6 cycloalkyl group.

According to some variants of the implementation of this invention CI! is C1-C4 alkyl substituted by one C1-C4 alkoxy group.

According to some variants of implementation of this invention, K1 is 1-methoxyethyl.

According to some variants of implementation of this invention, K1 is methoxymethyl.

According to some variants of the implementation of this invention CI! is C1-C4 alkyl substituted by one C3-C6 cycloalkyl group.

According to some variants of the implementation of this invention, Ki is 1-cyclopropoxyethyl.

According to some variants of implementation of this invention Ki is cyclopropoxymethyl.

According to some variants of implementation of this invention Ki is a C3-C06 cycloalkoxy group.

According to some variants of implementation of this invention K! is a cyclobutoxy group.

According to some variants of the implementation of this invention, K1 is a cyclopentyloxy group.

According to some variants of implementation of this invention KK! is a cyclopropoxy group.

According to some variants of implementation of this invention, K1 is a halogen.

According to some variants of implementation of this invention, K1 is chlorine.

According to some variants of implementation of this invention, K1 is fluorine.

According to some variants of the implementation of this invention, K2 is selected from the C1-C4 alkoxy group,

C3-C6 cycloalkoxy group and halogen.

According to some variants of implementation of this invention, K2 is a C1-C4 alkoxy group.

According to some variants of implementation of this invention, K2 is an isobutoxy group.

According to some variants of implementation of this invention, K2 is an isopropoxy group.

According to some variants of implementation of this invention, K2 is a methoxy group.

According to some variants of implementation of this invention, K2 is a C3-C06 cycloalkoxy group.

According to some variants of implementation of this invention, K2 is a cyclopropoxy group.

According to some variants of implementation of this invention, K2 is a halogen.

According to some variants of implementation of this invention, K2 is chlorine.

According to some variants of implementation of this invention, K2 is fluorine.

According to some variants of the implementation of this invention, K1 is selected from the C1-C4 alkoxy group, optionally substituted by one C3-C6 cycloalkyl substituent, C1-C4 alkyl substituted by one

With a substituent selected from a C1-C4 alkoxy group and a C3-Cb cycloalkoxy group, a C3-06 cycloalkoxy group and halogen; and K2 is selected from a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, and halogen.

According to some variants of the implementation of this invention, K1 is selected from the sec-butoxy group, xpro, cyclobutoxy group, cyclopentyloxy group, cyclopropoxy group, 1-cyclopropoxyethyl, cyclopropylmethoxy group, cyclopropoxymethyl, fluorine, methoxy group, 1-methoxyethyl and methoxymethyl; and K2 is selected from chlorine, cyclopropoxy group, fluorine, isobutoxy group, isopropoxy group and methoxy group.

According to some variants of implementation of this invention, the compound of Formula I is selected from: 6-(4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-isopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(cyclopentyloxy)phenyl)pyrimidine-4-carboxylic acid; (5)-6-(4-tert-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid; (8)-6-(4-tert-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(33-chloro-4-cyclobutoxyphenyl)pyrimidine-4-carboxylic acid; 6-(33-chloro-4-(cyclopropylmethoxy)phenyl)pyrimidine-4-carboxylic acid; 6-(33-chloro-4-(methoxymethyl)phenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(1-methoxyethyl)phenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(cyclopropoxymethyl)phenyl)pyrimidine-4-carboxylic acid; 6-(3-chloro-4-(1-cyclopropoxyethyl)phenyl)pyrimidine-4-carboxylic acid; 6-(4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(4-chloro-3-isopropoxyphenyl)pyrimidine-4-carboxylic acid; 6-(4-chloro-3-fluorophenyl)pyrimidine-4-carboxylic acid; 6-(33-chloro-4-fluorophenyl)pyrimidine-4-carboxylic acid; 6-(3,4-dichlorophenyl)pyrimidine-4-carboxylic acid; 6-(3,4-difluorophenyl)pyrimidine-4-carboxylic acid; and 6-(33-chloro-4-methoxy)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(d4-chloro-3-methoxyphenyl)pyrimidine-4-carboxylic acid. because According to some variants of implementation of this invention, the compound of Formula I is a 6-

(Z-chloro-4-isopropoxyphenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-(cyclopentyloxy)phenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is (5)-6-(4-tert-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is (K)-6-(4-second-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-cyclobutoxyphenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-(methoxymethyl)phenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-(1-methoxyethyl)phenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-(cyclopropoxymethyl)phenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-(1-cyclopropoxyethyl)phenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(d4-chloro-3-cyclopropoxyphenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(d4-chloro-3-isopropoxyphenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(d4-chloro-3-fluorophenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-fluorophenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3,4-dichlorophenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3,4-difluorophenyl)pyrimidine-4-carboxylic acid.

According to some variants of implementation of this invention, the compound of Formula I is 6-(3-chloro-4-methoxy)pyrimidine-4-carboxylic acid.

Also provided is a composition comprising an antiviral agent and a compound selected from the compounds shown in Table A below, or a pharmaceutically acceptable salt of said compound.

Table A

MM and AK oon pe and dgutu 6-(4-chloro-3-methoxy-phenyl)pyrimidinsi Ge) 4-carboxylic acid re;

LO

2 4 one 6-(3-chloro-4-isopropoxy-

Ah, Ge! phenyl)pyrimidine-4-carboxylic acid

SI

Table A

Chemical structure

her

Z-4one 6-(Z-chloro-4-(cyclopentyloxy)-o phenyl)pyrimidine-4-carboxylic acid e)

SI

her

A x 4 on (5)-6-(4-tert-butoxy-33-chlorane He) phenyl)pyrimidine-4-carboxylic acid (c) (4

Its in and OUN (B)-in-(4-second-butoxy-3-chlorophenyl)pyrimidine-4-carboxylic acid)

SI

Its four 6-(3-chloro-4-cyclopropoxy-

A Ge) phenyl) pyrimidine-4-carboxylic acid iv)

SI

If 7 4 on 6-(3-chloro-4-cyclobutoxy-

C He) phenyl) pyrimidine-4-carboxylic acid c)

SI

Its 4 that 6-(3-chloro-4-(cyclopropylmethoxy)- and He) phenyl)pyrimidine-4-carboxylic acid c)

SI

Its -4 6-(3-chloro-4-(methoxymethyl)- /o Ge)phenyl)pyrimidine-4-carboxylic acid

SI

Its 4-one 6-(3-chloro-4-(1-methoxyethyl)- /o He!phenyl)pyrimidine-4-carboxylic acid

SI

Her 14 4 on 6-(3-chloro-4-(cyclopropoxymethyl)-

He) He) phenyl) pyrimidine-4-carboxylic acid (o

Table A

Chemical structure

Mem 12 -4 that 6-(3-chloro-4-(1-cyclopropoxyethyl)-o o phenyl)pyrimidine-4-carboxylic acid

SI mm - on 13 o 6-(4-chloro-3-cyclopropoxy-

Gay phenyl)pyrimidine-4-carboxylic acid. Y mm - on 14 o 6-(4-chloro-3-isopropoxy-

SI phenyl)pyrimidine-4-carboxylic acid va

MM

-- Mr

Gee! 6-(4-chloro-3-isobutoxy-

SI phenyl)pyrimidine-4-carboxylic acid d mm iv y: on 6-(4-chloro-3-fluoro-phenyl)pyrimidine-4-

Gee! carboxylic acid

SI

Example 17: 6-(3-chloro-4-fluoro-phenyl)pyrimidin-4-o carboxylic acid

IS

SI mim 18: 6-(3,4-dichloro-phenyl)pyrimidin-4-o carboxylic acid

SI

SI mim 19 ha that 6-(3,4-difluoro-phenyl)pyrimidine-4-

Gee! carboxylic acid

IS

IS

Table A

Mo compounds Chemical structure Chemical name rilch

M »

Yes, he is. . 20 6-(3-chloro-4-methoxy)pyrimidine-4-

K o carboxylic acid c)

SI

Methods for preparing the compounds or pharmaceutically acceptable salts of the compounds described herein will be apparent to one of ordinary skill in the art, suitable procedures being described, for example, in the examples below and in the sources referenced herein.

This application proposes a method of treating a disorder in a subject infected with HIV, and said method includes additionally administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I: and

If - he is at 2

The formula or a pharmaceutically acceptable salt of the specified compound; and the specified subject is also administered an antiviral agent; and also:

A" and K? each independently selected from C1-C4 alkoxy group, optionally substituted by one

C3-C6 cycloalkyl substituent, C1-C6 alkyl substituted with one substituent selected from

C1-Cx alkoxy group and C3-Ce cycloalkoxy group, C3-Ce cycloalkoxy group and halogen.

This application proposes a method of reducing HIV viral load in a subject infected with HIV, and the specified method includes the additional administration of a therapeutically effective amount of a compound of Formula I to a subject in need of such treatment: xx

If to he in! at 2

The formula or a pharmaceutically acceptable salt of the specified compound; and the specified subject is also administered an antiviral agent; and also:

AB and K? each independently selected from a C1-C4 alkoxy group optionally substituted with one C3-C6 cycloalkyl substituent, a C1-C6 alkyl substituted with one substituent selected from a C1-C4 alkoxy group and a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl group and halogen.

Medicines against HIV are divided into six classes, depending on how the drug interferes with the life cycle of HIV. These six classes include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside inhibitors

Reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CSK5 antagonists, and integrase strand transfer inhibitors (LTIs). HIV uses reverse transcriptase (RT) to convert its RNA into DNA (reverse transcriptase). Blocking HT and reverse transcriptase prevents HIV replication. NRTIs lack a 3'-hydroxyl group, and these compounds are metabolically activated by host cell kinases into the corresponding 5'-triphosphate forms, which are then incorporated into DNA by HIV reverse transcriptase (RT) and act as terminators of the DNA synthesis chain. Examples of NRTIs include the drugs amdoxovir, Combivire,

Emtriva?, EpivirU, EpzicomU, Retrovir", tenofovir alafenamide fumarate, Trizivir,

Truvadag, Videx-7, Videx? EC, Vireadg", Zerit? and Ziagen?9. NNRTIs are non-competitive inhibitors of DNA polymerization, which bind to the hydrophobic pocket of HT near the active site of the polymerase. Examples of NRTIs include drugs Edurant-, Intelligence?,

lersivirin, RescriptoreU, Sustiva?, Viramun? and Weeramun? HA. After the transcriptase in the nucleus, the viral mRNA enters the cytoplasm and uses the host's cellular machinery to produce the viral protein. The virus components then assemble on the cell membrane, and the immature viruses bud off from the cell. Capsid proteins are produced as part of long polypeptides, which must be cleaved into shorter fragments by the protease enzyme to form mature functional proteins. IP binds to the site where the protein is cut, thereby preventing the release of individual capsid proteins by the enzyme. As a result, new viral particles become unable to mature or become infected. Examples of PIs include the drugs Aptivus?7, Crixivang-, Invirase?, Kaletra?,

Lexiva?, Norvir?, Prezista?, Reataz? and Viracept?U. Fusion inhibitors prevent the HIV envelope from joining the host cell membrane (fusion), which prevents HIV from entering the host cell. An example of fusion inhibitors is the drug Fuseon?. CSK5 antagonists block the CSK5 receptor on the surface of certain immune cells, such as CO4 cells, which prevents HIV from entering cells. Examples of SSK5 antagonists include the drugs senecrivir and

Selzentre?. IPLs block integrase, an enzyme that HIV uses to incorporate (insert) viral DNA into the DNA of host cells. Blocking integrase prevents HIV replication.

Examples of IPLs include Isentress?, Tyvikai? and ElvitegravirU. Combinations of drugs of different classes include drugs Atripla? (efavirenz and tenofovir and emtricitabine), Complera? (rilpivirine - tenofovir and emtricitabine), Stribild? (elvitegravir and cobicistat and tenofovir and emtricitabine) and Trii"m (dolutegravir and abacavir and lamivudine).

Recommended antiretroviral therapy (ART) regimens for the treatment of HIV include the use of a combination of three or more antiretroviral (ARV) drugs from at least two different HIV drug classes. The currently accepted standard of HIV/AIDS treatment in developed countries is highly active antiretroviral therapy (HAARTV), usually a combination of two reverse transcriptase inhibitors and a protease inhibitor. Class-reserved regimens intentionally exclude all ARV drugs of a specific drug class to preserve specific ARV drugs for future use in case the regimen needs to be changed due to toxicity or drug resistance. Mode with class reservation is also possible

To be used to avoid unwanted effects associated with a specific class of drugs. Certain HIV ART regimens include a pharmacokinetic enhancer that increases the blood levels of certain ARV drugs and makes these drugs more effective. Examples of pharmacokinetic enhancers include drugs Cobicistat?, a component of the approved combination with fixed dosages in the form of tablets Stribild?7; ritonavir, an PI improving the pharmacokinetics (PK) profiles of concomitant PIs; and 5RI-452. Experimental options for HIV therapy on an immune basis include the drugs Aralene, DermavVir-, interleukin-7, Lexgenleicel-T (Iehdepieise!-T), PlaquenileU, Proleukin? and 5B-728-T. Transfer inhibitors are a class

ARV drugs, which include fusion inhibitors, CSE5 antagonists, and glycosidase inhibitors.

Maturation inhibitors are a class of ARV drugs that target the dad precursor polyprotein, the main structural protein responsible for the assembly and unfolding of virion particles during maturation.

According to some embodiments of the present invention, the antiviral agent is selected from entry inhibitors, fusion inhibitors, glycosidase inhibitors, SSR antagonists, immune-based therapy options, integrase inhibitors, maturation inhibitors, combinations of drugs of different classes, non-nucleoside reverse transcriptase inhibitors, nucleoside/nucleotide inhibitors reverse transcriptase, pharmacokinetic enhancers and protease inhibitors, as well as combinations of these agents.

According to some embodiments of the present invention, the antiviral agent is selected from nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CSE5 antagonists, and integrase chain transfer inhibitors, as well as combinations of these agents.

According to some variants of implementation of this invention, the antiviral agent is selected from the group that includes drugs: amdoxovir, Aptivus?, Aralen, Atripla, senecriviroc,

Cobicistat", KombivirU, Complerae, Krixivan-, DermavVir-, Edurant", Elvitegravir, Emtriva?,

Epivir?, EpzikomU, Fuseone, ibalizumab, Intelens?, interleukin-7, Inviraza?, Isentress?,

Kaletra?e, lersivirine, lexgenleucel-T, Leksivaye, Norvire, PlaquenileU, Proleukine, Prezystaye?,

RKO 140, Rescriptore, Retrovir?U, Reataze, 58-728-Y, Selzentry?, 5RI-452, Strybilde,

Sustiva?, tenofovir alafenamide fumarate, Tyvikay?, Trii M, TrizivirU, Truvadagye, Videx?,

Videx? ES, Viracept", Viramun-, Viramun? XE, Viread-, Zerit? and Ziagene, as well as combinations of 60 of the indicated means.

According to some variants of the implementation of this invention, the antiviral agent is

VAARVT.

Human immunodeficiency virus (HIV) is a virus that causes acquired immunodeficiency syndrome (AIDS), which is the most advanced stage of HIV infection. HIV destroys COA(u) T-lymphocytes (CO4(g)-cells) of the immune system, as a result of which the body becomes vulnerable to life-threatening infections and variants of cancer. HIV is a retrovirus divided into two subtypes: HIV-1 and HIV-2. Both types are transmitted through direct contact with HIV-infected body fluids, such as blood, semen, and genital secretions, or from an HIV-infected mother to her child during pregnancy, childbirth, or breastfeeding (through breast milk). HIV-1 can be divided into four groups: Group M, Group M,

Group O and Group R. Viruses within each group can then be further subdivided into subtypes. For example, the HIV-1 M group includes at least nine subtypes: A1, A2, B, C, 0, P1,

E2, O, H, U and K. HIV-2 infection is endemic to West Africa. This infection usually progresses to HIV/AIDS with clinical symptoms over a longer period of time and is characterized by a lower mortality rate than HIV-1 infection.

According to some variants of implementation of this invention, HIV is HIV-1.

According to some variants of implementation of this invention, HIV is HIV-1 of the M group.

According to some variants of implementation of this invention, HIV is HIV-1 group M subtype AT.

According to some variants of implementation of this invention, HIV is HIV-1 of group M of subtype A2.

According to some variants of implementation of this invention, HIV is HIV-1 group M subtype B.

According to some variants of implementation of this invention, HIV is HIV-1 of group M of subtype C.

According to some variants of implementation of this invention, HIV is HIV-1 group M subtype 0.

According to some variants of implementation of this invention, HIV is HIV-1 of group M of subtype E1.

According to some variants of implementation of this invention, HIV is HIV-1 of group M of subtype E2.

According to some variants of implementation of this invention, HIV is HIV-1 group M subtype 0.

According to some variants of implementation of this invention, HIV is HIV-1 of group M of subtype H.

According to some variants of implementation of this invention, HIV is HIV-1 group M subtype 5.

According to some variants of implementation of this invention, HIV is HIV-1 of group M of subtype K.

According to some variants of implementation of this invention, HIV is HIV-1 of the M group.

According to some variants of implementation of this invention, HIV is HIV-1 group 0.

According to some variants of implementation of this invention, HIV is HIV-1 of the R group.

According to some variants of implementation of this invention, HIV is HIV-2.

HIV enters the central nervous system (CNS) early in the infection process and during the course of the disease causes several important CNS conditions such as HIV encephalopathy and complex

AIDS dementia. As part of the acute HIV syndrome in the process of seroconversion, patients may have HIV encephalopathy. HIV-associated progressive encephalopathy (PEE) is a complex syndrome characterized by cognitive, motor, and behavioral features observed in children. Before the advent of highly active antiretroviral therapy (HAART), dementia was a common cause of morbidity and mortality in HIV-infected patients. This disease was usually observed in the late stages of AIDS, when the number of bra(z)-lymphocytes becomes less than 200 cells/ml, and was recorded in up to 50 95 patients before death. In 1986, the term "AIDS-dementia complex" (SCD) was coined to describe a unique set of neurobehavioral findings. HIV-associated neurocognitive disorders (NANDs) encompass a hierarchy of progressive, more severe forms of neurological damage.

These lesions can range from asymptomatic neurocognitive impairment (NID) to mild neurocognitive disorder (NID) to more severe HIV-associated dementia (ADD) (also called SNiD-dementia complex or HIV-encephalopathy). COD is considered as a single disease with a wide and diverse spectrum of clinical manifestations and severity. COD is characterized by cognitive, motor and behavioral features in adults, usually with progressive SNiD. With the advent of VAARVT, a less severe dysfunction than CSD - moderate cognitive motor disorder (MCD) - has become more common. The overall psychosocial and emotional burden on family and friends of patients with HIV dementia is enormous and far exceeds that of a cognitively intact patient with AIDS. In patients with cognitive difficulties, there are problems with compliance and adherence to the medication schedule. Because of their psychoneurological problems, these patients are likely to be less inhibited and more likely to engage in risky HIV-related behaviors (eg, unprotected sex) and, as a result, are at greater risk of transmitting the virus. In addition to HIV itself, other causes of neurological complications in HIV-infected individuals include opportunistic tumor infections and antiretroviral drugs. Other neurologic complications that occur as a result of primary HIV infection include vacuolar myelopathy, peripheral neuropathies, and polymyositis.

According to some embodiments of the present invention, the HIV-related disorder is an opportunistic infection selected from candidiasis, coccidioidomycosis, cryptococcosis, cryptosporidiosis, cytomegalovirus, herpes simplex virus, herpes zoster, histoplasmosis, isosporosis, Musobasiegt amisht complex, pneumocystis pneumonia , bacterial pneumonia, progressive multifocal leukoencephalopathy Zaytopegia, toxoplasmosis and tuberculosis.

According to some embodiments of the present invention, the HIV-related disorder is an AIDS-related cancer selected from cervical cancer, Kaposi's sarcoma, and lymphoma.

According to some embodiments of the present invention, the HIV-related disorder is a disease indicative of AIDS, which is selected from the group consisting of: candidiasis of the esophagus, bronchi, trachea or lungs, invasive cancer of the cervix, disseminated or extrapulmonary coccidioidomycosis, extrapulmonary cryptococcosis, chronic intestinal cryptosporidiosis, cytomegalovirus disease (other than liver, spleen, or nodules), cytomegalovirus retinitis with vision loss, HIV-related encephalopathy, herpes simplex (with chronic ulcers, bronchitis, pneumonitis, or esophagitis), disseminated or extrapulmonary histoplasmosis, chronic intestinal

From isosporosis, Kaposi's sarcoma, Burkitt's lymphoma, immunoblastic lymphoma, primary brain lymphoma, disseminated or extrapulmonary Musobasiegisht amisht complex or M.

Kapzabzia, pulmonary or extrapulmonary Musobasiegisht shibegscio5ikh5, disseminated or extrapulmonary species of the genus Musobasiegisht, Jirovets pneumocystis pneumonia, recurrent pneumonia, progressive multifocal leukoencephalopathy, recurrent salmonellosis septicemia, brain toxoplasmosis and wasting syndrome caused by HIV.

According to some embodiments of the present invention, the disorder associated with HIV is a neurological disorder.

According to some variants of implementation of this invention, the neurological disorder is selected from the AIDS-dementia complex, SNiD-induced encephalopathy, HIV-encephalopathy, HIV-associated progressive encephalopathy, HIV-associated neurocognitive disorder, asymptomatic neurocognitive impairment, moderate neurocognitive disorder, HIV-associated dementia, moderate cognitive motor disorder, vacuolar myelopathy, peripheral neuropathy and polymyositis.

According to some variants of the implementation of this invention, the neurological disorder is the AIDS-dementia complex.

According to some variants of implementation of this invention, the neurological disorder is AIDS-induced encephalopathy.

According to some variants of implementation of this invention, a neurological disorder is

HIV encephalopathy.

According to some variants of implementation of this invention, a neurological disorder is

HIV-associated progressive encephalopathy.

According to some variants of implementation of this invention, a neurological disorder is

HIV-associated neurocognitive disorder.

According to some variants of implementation of this invention, a neurological disorder is an asymptomatic neurocognitive impairment.

According to some embodiments of the present invention, the neurological disorder is a moderate neurocognitive disorder.

According to some variants of the implementation of this invention, the neurological disorder is a moderate cognitive movement disorder. because according to some variants of implementation of this invention, the neurological disorder is vacuolar myelopathy.

According to some variants of implementation of this invention, the neurological disorder is peripheral neuropathy.

According to some variants of implementation of this invention, the neurological disorder is polymyositis.

The combination of a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent in the composition may be physical or non-physical. Examples of physically associated compositions include: compositions (for example, in one composition) containing a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent in a mixture (for example, in the same single dose); compositions containing a substance in which a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent are chemically/physicochemically linked (eg, by cross-linking, molecular agglomeration, or binding to a common carrier group ); compositions containing a substance in which a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent are co-packaged chemically/physicochemically (e.g., coated on or in lipid vesicles, particles (e.g., micro- or nanoparticles) or emulsion drops); and pharmaceutical kits, pharmaceutical packages, or patient packages in which a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent are co-packaged or co-offered (eg, as part of a single-dose combination).

Examples of non-physically associated compositions include: a substance (eg, not in the same formulation) containing a compound or a pharmaceutically acceptable salt of a compound described herein, or an antiviral agent together with instructions for combining the compound or a pharmaceutically acceptable of the salt of the compound described in this application and the antiviral agent immediately before taking with the formation of a physical connection of both specified compounds; a substance (eg, which is not in the same composition) containing a compound or a pharmaceutically acceptable salt of a compound described in this application, or an antiviral agent together with instructions for additional therapy with a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent ; a substance containing a compound or

From a pharmaceutically acceptable salt of a compound described in this application, or an antiviral agent with instructions for administration to a patient population that has been administered (or is being administered) other compounds or a pharmaceutically acceptable salt of the compounds described in this application, or an antiviral agent; and a substance containing a compound or a pharmaceutically acceptable salt of a compound described in this application, or an antiviral agent in an amount or form that is specifically adapted for use in combination with another compound or a pharmaceutically acceptable salt of a compound described in this application, or an antiviral agent .

Packaged compositions are also offered. Such packaged compositions contain a pharmaceutical composition containing at least one compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent and instructions for using the composition to treat a subject (typically a human patient). According to some embodiments of the present invention, the instructions are instructions for using a pharmaceutical composition to treat a subject suffering from an HIV-related disorder. According to some embodiments of the present invention, the instructions are instructions for using a pharmaceutical composition for the treatment of a subject suffering from an HIV-related neurological disorder.

The packaged pharmaceutical composition may include the provision of application information, for example, to the patient or healthcare professionals; or this information may be presented in the form of a label on the packaged pharmaceutical composition. Application information may include, for example, information on efficacy, dosage and administration, contraindications, and adverse reactions related to the pharmaceutical composition.

According to some variants of implementation of this invention, the compound of Formula !| or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent: a) are in a mixture; B) connected chemically/physico-chemically; c) packed together by a chemical/physico-chemical method; or (4) not mixed but packaged together or offered together.

According to some variants of implementation of this invention, the compound of Formula !| or a pharmaceutically acceptable salt of a compound described herein and an antiviral agent are in the mixture.

According to some variants of the implementation of this invention, the compound of Formula 1/ or a pharmaceutically acceptable salt of the compound described in this application and the antiviral agent are connected by a chemical/physico-chemical method.

According to some variants of implementation of this invention, the compound of Formula !/ or a pharmaceutically acceptable salt of the compound described in this application and the antiviral agent are packaged together by a chemical/physicochemical method.

According to some variants of implementation of this invention, the compound of Formula i! or a pharmaceutically acceptable salt of a compound described in this application and the antiviral agent are not mixed, but packaged together or offered together.

According to some embodiments of the present invention, the compound of Formula 1/ or a pharmaceutically acceptable salt of the compound described in this application and the antiviral agent are packaged together in one container or in several containers in one outer package.

According to some variants of implementation of this invention, the compound of Formula !| or a pharmaceutically acceptable salt of a compound described in this application is administered prior to the administration of an antiviral agent.

According to some variants of the implementation of this invention, the compound of Formula 1/ or a pharmaceutically acceptable salt of the compound described in this application is administered after the introduction of an antiviral agent.

According to some variants of the implementation of this invention, the compound of Formula 1/ or a pharmaceutically acceptable salt of the compound described in this application and the antiviral agent are administered simultaneously.

According to some embodiments of the present invention, an antiviral agent and a compound

Formulas I or a pharmaceutically acceptable salt of the compound described in this application are administered simultaneously in one composition.

According to some embodiments of the present invention, an antiviral agent and a compound

Formulas I or a pharmaceutically acceptable salt of the compound described in this application are administered simultaneously in different formulations.

According to some embodiments of the present invention, an antiviral agent and a compound

Formula I or a pharmaceutically acceptable salt of a compound described in this application are contained in a copackaged medicinal product.

Generally, a compound or a pharmaceutically acceptable salt of a compound described in this application and an antiviral agent will be administered in therapeutically effective amounts by any of the acceptable routes of administration that are intended for similar use. The actual amounts of a compound or a pharmaceutically acceptable salt of a compound described herein and the antiviral agent, i.e., the active ingredients, will depend on a variety of factors, such as the severity of the disease being treated, the age and relative health of the subject, the activity of the compounds, route and form of administration, and other factors well known to those skilled in the art. The active ingredients can be administered at least once a day, for example once or twice a day.

According to some embodiments of the present invention, the compound or a pharmaceutically acceptable salt of the compound described in this application and/or an antiviral agent is administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions containing a compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent together with at least one pharmaceutically acceptable excipient selected from carriers, excipients, and excipients are provided.

Pharmaceutically acceptable excipients must be of a sufficiently high degree of purity and a sufficiently low degree of toxicity to be suitable for administration to the animal being treated. The excipient may be inert or may have pharmaceutical benefits. The amount of excipient used in combination with a compound or a pharmaceutically acceptable salt of a compound described in this application and/or with an antiviral agent is sufficient to provide a convenient amount of substance for administration per single dose of the compound or a pharmaceutically acceptable salt of a compound described in this application, and/or an antiviral agent.

Examples of pharmaceutically acceptable carriers or components of said carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered tragacanth, malt, gelatin, talc, solid lubricants such as stearic acid and magnesium stearate, calcium sulfate, synthetic oils; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol, alginic acid, phosphate buffer solutions, emulsifiers such as TM/EEM5, wetting agents such as sodium lauryl sulfate, dyes; flavor additives, 60 components for tableting, stabilizers, antioxidants, preservatives, pyrogen-free water,

isotonic saline solution and phosphate buffer solutions.

The pharmaceutical composition may include optional active substances that do not substantially interfere with the activity of the compound or a pharmaceutically acceptable salt of the compound described in this application and/or the antiviral agent.

Effective concentrations of a compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent are mixed with a suitable pharmaceutically acceptable excipient. In cases where a compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent exhibits insufficient solubility, methods of solubilization of the compounds can be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethylsulfoxide (0M50O), the use of surfactants such as TUMEE, or dissolution in aqueous sodium bicarbonate.

After mixing or adding a compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on a number of factors, including the intended route of administration and the solubility of the compound or a pharmaceutically acceptable salt of the compound described herein and the antiviral agent in the vehicle selected.An effective concentration sufficient to alleviate the symptoms of the disease being treated can be determined empirically.

A compound or a pharmaceutically acceptable salt of a compound described herein and an antiviral agent may be administered orally, topically, parenterally, intravenously, by intramuscular injection by inhalation or spray, sublingually, transdermally, by buccal administration, rectally, as ophthalmic solution or by other methods in formulations with dosage units.

Pharmaceutical compositions can be prepared in formulations for oral administration, such as, for example, tablets, lozenges, cakes, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs.

Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for the manufacture of pharmaceutical

Of the compositions, and such compositions may contain one or more substances, such as sweeteners, flavorings, colorants and preservatives, to obtain pharmaceutically convenient and palatable preparations. According to some variants of implementation of this invention, pharmaceutical compositions for oral administration contain from 0.1 to 99% of a compound or a pharmaceutically acceptable salt of a compound described in this application, and/or an antiviral agent. According to some variants of implementation of this invention, pharmaceutical compositions for oral use contain at least 5 95 (wt. 95) of a compound or a pharmaceutically acceptable salt of a compound described in this application, and/or an antiviral agent. Some embodiments of this invention contain from 25 95 to 50 95 or from 595 to 7595 of a compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent.

Pharmaceutical compositions for oral use also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, etc. Pharmaceutically acceptable carriers suitable for such compositions are well known in the art. Pharmaceutical compositions for oral administration may contain preservatives, flavors, sweeteners such as sucrose or saccharin, taste masking agents, and coloring agents.

Typical carrier components for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. Syrups and elixirs can be formulated with sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. These pharmaceutical compositions may also contain an agent that reduces irritation.

A compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent may be incorporated into liquid preparations for oral administration, such as, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. Moreover, pharmaceutical compositions containing a compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent may be presented as a dry product intended for reconstitution with water or other suitable excipient prior to use. Such liquid preparations may contain conventional additives such as suspending agents (eg, sorbitol syrup, methylcellulose, 60 glucose/agar, syrup, gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminum stearate gel and hydrogenated edible fats), emulsifying agents (eg, lecithin, sorbitan monooleate or gum arabic), non-aqueous fillers that may include edible oils (eg, almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethyl alcohol) and preservatives (eg, methyl- or propyl-p-hydroxybenzoate and sorbic acid).

In the case of suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Amise! KS-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate.

Aqueous suspensions contain a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents; naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxyethanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as a polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, a polyethylene sorbitan substitute. Aqueous suspensions may also contain one or more preservatives, for example, ethyl- or n-propyl-p-hydroxybenzoate.

Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oil suspensions may contain a thickener, for example, beeswax, solid paraffin or cetyl alcohol. Sweetening agents, such as those listed above, and flavoring agents may be added to provide palatable oral preparations. Data

Pharmaceutical compositions can be preserved by adding an antioxidant such as ascorbic acid.

Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin, or a mixture of these oils. Suitable emulsifying agents may be naturally occurring gums such as gum arabic or tragacanth, naturally occurring phosphatides such as soybean, lecithin and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monooleate , as well as condensation products of these partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.

Dispersible powders and granules suitable for obtaining an aqueous suspension on the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are presented above.

Tablets generally contain conventional pharmaceutically acceptable excipients such as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; leavening agents such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. To improve the flow characteristics of the powder mixture, you can use substances that promote sliding, such as silicon dioxide. Dyes, such as ROS dyes, may be added to achieve the desired appearance.

Sweeteners and flavors such as aspartame, saccharin, menthol, peppermint, and fruit flavors can be effective adjuvants for chewable tablets. Capsules (including sustained-release and extended-release formulations) typically contain one or more of the above solid diluents.

The choice of carrier components often depends on side effects such as taste, cost, and storage stability.

Such pharmaceutical compositions may also be coated by conventional methods, typically with pH- or time-dependent coatings, such that the compound or a pharmaceutically acceptable salt of a compound described herein and/or the antiviral agent is released in the gastrointestinal tract near the the required area of application or at different time periods to extend the required action. Such dosage forms generally include, but are not limited to, one or more components selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, coatings

Ashagats, waxes and shellac.

Pharmaceutical compositions for oral administration may also be presented in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with aqueous or oily medium, for example, peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions can be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated in accordance with the known state of the art using those suitable dispersing or wetting agents and suspending agents mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic initially acceptable excipient, for example, such as a solution in 1,3-butanediol. Acceptable excipients that may be used include water, Ringer's solution, and isotonic sodium chloride solution.

In addition, sterile non-volatile oils are traditionally used as a solvent or suspending medium. Any soft non-volatile oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used to produce injectable drugs.

A compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent can be administered parenterally in a sterile environment.

Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrathecal injection or infusion methods. A compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent depending on the excipient and concentration used may be either suspended or dissolved in the excipient. It is advantageous when excipients such as anesthetic agents, preservatives and buffering agents can be dissolved in the excipient. In many pharmaceutical formulations

Zo for parenteral administration of the carrier contains at least 90 wt. 95 from the entire composition. According to some embodiments of the present invention, the carrier for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.

A compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent can also be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. These materials include cocoa butter and polyethylene glycols.

A compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent may be formulated into a composition for topical or external use, for example, for topical application to the skin and mucous membranes such as the eyes, in the form of gels, creams and lotions, and can also be prescribed for injection into the eye.

Topical pharmaceutical compositions can be in any form, including, for example, solutions, creams, ointments, gels, lotions, lotions, cleansers, moisturizers, sprays, skin patches, and the like.

Such solutions can be prepared in the form of 0.01 Fo - 10 Fo isotonic solutions, pH 5-7, using suitable salts. It is also possible to formulate a compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent intended for transdermal administration in the form of a transdermal patch.

Topical pharmaceutical compositions containing at least one compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent can be mixed with a variety of carriers well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerin, vitamins A and E in oil, mineral oil, propylene glycol, PPG-2 myristyl propionate, etc.

Other substances suitable for use in carriers for topical preparations include, for example, emollients, solvents, wetting agents, thickeners and powders. Examples of each of these types of substances that can be used alone or as a mixture of one or more substances are the following substances: for Typical emollients include stearyl alcohol, glyceryl monoricinoleate,

glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol , cetyl palmitate, dimethyl polysiloxane, di-n-butyl sebacinate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid , palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and myristyl myristate; propellants such as propane, butane, isobutane, dimethyl ether, carbon dioxide and nitrous oxide; solvents such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran; humectants such as glycerol, sorbitol, sodium 2-pyrrolidone-o-carboxylate, soluble collagen, dibutyl phthalate and gelatin, and powders such as chalk, talc, fuller's earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectites, trialkylarylammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fused silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol monostearate.

A compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent may also be administered topically in the form of liposome-based delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, and phosphatidylcholines.

Other pharmaceutical compositions suitable for providing systemic delivery of a compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent include sublingual, buccal, and nasal dosage forms. Such pharmaceutical compositions typically contain one or more soluble excipients such as sucrose, sorbitol, and mannitol, and binders such as gum arabic, microcrystalline

Zo cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. The glidants, lubricants, sweeteners, colors, antioxidants, and flavors described above may also be included.

Pharmaceutical compositions for inhalation, as a rule, can be presented in the form of a solution, suspension or emulsion, which can be administered as a dry powder or in the form of an aerosol using a commonly accepted propellant (for example, dichlorodifluoromethane or trichlorofluoromethane).

Pharmaceutical compositions may also optionally contain an activity enhancer.

The activity enhancer can be selected from a wide variety of molecules that act in different ways to enhance the therapeutic effects or to make said substances independent of the therapeutic effects of the compound or a pharmaceutically acceptable salt of the compound described in this application and/or the antiviral agent. Specific classes of activity enhancers include skin penetration enhancers and absorption enhancers.

Pharmaceutical compositions may also contain additional active agents that can be selected from a wide variety of molecules that can act in different ways to enhance the therapeutic effects of a compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent. These optional other active agents, if available, are usually used in pharmaceutical compositions at a level varying from 0.01 95 to 15 95. Some embodiments of the present invention contain from 0.1 95 to 10 95 by weight of the composition.

Other variants of implementation of this invention contain from 0.5 95 to 5 95 by weight of the composition.

In all of the above-described cases, the compound or a pharmaceutically acceptable salt of the compound described in this application, or the antiviral agent can be administered in combination with other active agents.

When used in combination with one or more additional pharmaceutical agents, a compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent may be administered before, simultaneously with, or after the administration of the additional pharmaceutical agent or agents.

Doses of the compounds described herein depend on a variety of factors, including the specific syndrome being treated, severity of symptoms, route of administration, frequency of dosing interval, specific compound used, efficacy, toxicological profile, pharmacokinetic profile of the compound, and presence of any adverse effects. side effects, in addition to other considerations.

A compound or a pharmaceutically acceptable salt of a compound described herein and an antiviral agent are typically administered at dose levels and in a manner generally accepted for CMO inhibitors and antiviral agents, respectively. For example, a compound or a pharmaceutically acceptable salt of a compound described herein and/or an antiviral agent may be administered in one or more doses by oral administration at a dose level, typically 0.001-100 mg/kg/day, e.g., 0, 01-100 mg/kg/day, eg 0.1-70 mg/kg/day, eg 0.5-10 mg/kg/day. Unit dosage forms may contain, as a rule, 0.01-1000 mg of a compound or a pharmaceutically acceptable salt of a compound described in this application and/or an antiviral agent, for example, 0.1-50 mg of at least one compound or a pharmaceutically acceptable salt of a compound, described in this application, and/or an antiviral agent. For intravenous administration, at least one compound or a pharmaceutically acceptable salt of a compound described in this application, and/or an antiviral agent can be administered in one or more doses at a dose level, for example, 0.001-50 mg/kg/day, e.g., 0.001-10 mg/kg/day, e.g., 0.01-1 mg/kg/day Unit dosage forms may contain, e.g., 0.1-140 mg of a compound or a pharmaceutically acceptable salt a compound described in this application and/or an antiviral agent.

When performing the procedures of the methods described in this application, of course, it should be understood that the mention of specific buffers, media, reagents, cells, cultivation conditions, etc. are not limiting, and should be understood to include all similar material that one of ordinary skill in the art would find of interest or value in the particular context in which this discussion is presented. For example, it is often possible to substitute one buffer system or culture medium for another and obtain similar, if not identical, results. Those skilled in the art have sufficient knowledge of such systems and methodologies to be able, without excessive experimentation, to make the specified substitutions, which will optimally serve to achieve the goals when applying the methods and procedures disclosed in this application.

Examples

The compounds, pharmaceutically acceptable salts and prodrugs of the compounds described in this application, compositions and methods described in this application are further illustrated by the following non-limiting examples.

In this application, the following abbreviations have the following meanings. If the definition of an abbreviation is not given, this abbreviation has, as a rule, a generally accepted meaning.

OSM - dichloromethane

OME-M,M-dimethylformamide

OM5O - dimethyl sulfoxide

ECOAc - ethyl acetate g gram h. - an hour, hours

LC/MS - liquid chromatography/mass spectrometry mg - milligram waves. - minutes ml - milliliter mmol - millimoles

MM - millimolar nm - nanometer c.t. 5 room temperature

TVME :- methyl t-butyl ether

TNE "- tetrahydrofuran μl - microliter

MKM - micromolar 1g/L1Mml - 1 volume

Experiments

Commercially available reagents and solvents (HPLC grade) were used without further purification.

Analysis by thin-layer chromatography (TLC) was performed on Kieseide plates! 60

E254 (MegsK) and visualized using UV light. Reactions using microwave radiation were carried out using a focused microwave radiation SEM device.

Analytical HPLC-MS was carried out with the help of Adiyepi HP1100 and Zpitaa?y 2010 systems with the use of Aiapiiz a8C18 columns with a reversed phase (5 μm, 2.1x50 mm), a gradient of 5-100 95 V bo (A - water/0.1 96 ant acid, B - acetonitrile/0.1 95 formic acid) for 3 minutes, injection volume 3 μl, flow rate - 1.0 ml/min. The UV spectrum was read at a wavelength of 215 nm using a two-wavelength UV detector Mu/aieg5 2487 or a 5pitaai7y 2010 system. Mass spectra were obtained in the range of the mass-charge ratio (t/7) from 150 to 850 at a spectrum recording speed of 2 scans per second using a Umayeg5 2MO detector and in the range of t/2 from 100 to 1000 at a spectrum recording rate of 2 Hz using electrospray ionization using the ZPitaydly 2010 LC-MS system, or analytical HPLC-MS was performed using the Adiyepi HP1100 and 5ypitay?7y systems 2010 using reversed-phase columns Umaieg AMapiiz aC18 (Z μm, 2.1x100 mm), gradient 5-100 90 V (A - water/0.1 96 formic acid, B - acetonitrile/0.1 95 formic acid) during 7 min., injection volume C μl, flow - 0.6 ml/min. The UV spectrum was read at a wavelength of 215 nm using a Umayegye 2996 photodiode matrix or using the Zpitai7y 2010 system. Mass spectra were obtained in the range of t/7 from 150 to 850 at a spectrum recording speed of 2 scans per second using a Umayegye5 detector 20) and in the t/2 range from 100 to 1000 at a spectrum recording speed of 2 Hz using electrospray ionization using the Zpitad7y 2010 RH-MS system. The data were summarized and presented using Orepi software

Orepi/uph Vhom/zeg or using software 5pitaaiy RzirRogi.

Example 1

Scheme of reaction 1 shchi to shhe

B with B: he M «o with M tu, a

Not ober x pi 7 - z nin det no i

Y Y Stadin and Shchi and; and Staliya 2 still and kodele and x her x Ei pnshchi

Stage Z i schu I di EY xx

Reaction scheme 1, stage 1. To a stirred suspension of dichloropyrimidine (1 equiv. (equivalent)) in 1,4-dioxane (15 vol. (volumes)) was added boronic acid (0.7 equiv.) and RD(RRIZ3) 4 (0.025 eq.).

A 2 M solution of K2SOZ (7.5 vol.) was added to the resulting mixture and heated at a temperature of 90 °C overnight in an M2 atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a mixture of EIOAc:water (1:1 ) (100 vol.), and the resulting solution was filtered through celite. The organic layer was separated, then the aqueous layer was extracted with EtOAc (50 vol.). The combined organic layers were washed with saturated aqueous Mass (20 vol.), dried over Ma2O4, filtered, and the solvent was removed in vacuo.The resulting residue was purified by flash column chromatography (eluent: |from 0:11 to 1:19)

With ECHOAc:heptane) to obtain the desired target compound.

Reaction scheme 1, step 2. 4-Chloro-6-substituted-phenyl-pyrimidine (1 equiv), RasCIg(arr)OsCM (0.05 equiv) and triethylamine (2 equiv) were suspended in degassed MeOH (50 vol .) in a bomb equipped with a magnetic stirrer. The atmosphere in the reaction vessel was replaced with M2 by sequential vacuuming and injection of M2 gas (this process was repeated three times). The bomb was then purged with CO by sequential CO injection and vacuuming. The vessel was pressurized to 5 bar of CO, and the vessel was heated at 50 °C with stirring for 5 h. The reaction vessel was allowed to cool to room temperature before being purged with CO and charged with M2. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EIOAc (30 vol) and water (30 vol). The solution was filtered through cotton wool, and the organic layer was separated, washed with saturated aqueous Mass (15 vol), dried over Ma 2 5 O 4 , filtered and concentrated under reduced pressure. eluent: |from 0:1 to 1:9| EtOAc:heptane) resulted in obtaining the target compound.

Reaction scheme 1, stage 3. b6-substituted-phenyl-pyrimidine-4-carboxylic acid methyl ester (1 eq.) was suspended in MeOH (20 0.06 b.), 1 M Mahon solution (20 vol.) and stirred at room temperature within 4 hours. The reaction mixture was acidified with 2 M HCl.

Soluble products were extracted with OSM (2x20 vol.), and the combined organic layers were dried over

Mo and filtered; concentration under reduced pressure afforded the target compound. The insoluble products were filtered, washed with water (3x10 vol.) and heptane (3x10 vol.), then dried under vacuum to give the target compound.

The following compounds were prepared essentially as described above. mass spectrometry mm -d on (MANI - 265/267, 100 95 1 o 264.67 with retention time - 3.53

SI and 3.70 minutes. re;

MM

Level of oBob3 /MeNI - 253, 100 95 with holding time - 4.06 minutes.

SI

IS

MM

F | on IM-ANI" - 253, 100 95 at 17,252.63 holding time - 3.92 -

E io) 4.23 minutes.

SI

MM iv y: on 269.09 (Men - 269, 100 95 at

Gee! and retention time - 4.04 minutes.

SI

SI mtm on iv and: ozviv 0 MN - 237, 100 95 at

Ge) and retention time - 3.74 minutes.

IS

IS

MM same | on IM-ANI" - 265, 100 95 at 20 264.67 retention time - 3.73 -

From o) 4.10 minutes.

SI

Example 2

The scheme of the reaction of the 2nd layer of the VO kh i whose chu o this m zh i neck ooooeetesesssssoooetttni

Stage And Stage? 00000 Stage 3 5 z Z M yam M m r cho eh odi rev sy i "KI

Stage UC Stage 5 OT Yetalinb vk

Reaction scheme 2, stage 1. Dibromo(triphenyl)phosphorane (1.2 equiv.) was added to E-OH (1 equiv.) in OSM (70 vol.) at a temperature of 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The solvent was removed in vacuo. YuSM (10 vol.) was added to the reaction mixture. The precipitate was filtered to give the target compound.

The crude mixture was used in the next step without additional purification.

Reaction scheme 2, stage 2. 2-Chloro-4-iodophenol (1 equiv) and С52СО3 (2.5 equiv) were added to E-Vg (1.1 equiv.) in OME (15 vol.). The reaction mixture was heated in a reflux flask for 3 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, BAS (40 vol.) and aqueous ammonium (40 vol.) were added. The organic layer was separated, and then the aqueous layer was extracted with EtOAc (50 vol.). The combined organic layers were washed with saturated aqueous Mass (20 vol), dried over Ma 2 CO 3 , filtered, and the solvent was removed in vacuo. The resulting residue was purified by column flash chromatography (eluent: I3:1 | EtOAc:heptane) to obtain the desired target compound.

Reaction scheme 2, stage 3. To a stirred suspension of 4-substituted-3Z-chloroiodobenzene (1 equiv.) in degassed OME (15 vol.) was added bis-diborane (1.05 equiv.), RD(ОАсС)2 ( 0.04 equiv.) and

COAc (3.0 equiv.). The reaction mixture was heated at a temperature of 90 °C for 5 hours in the atmosphere

M2. The reaction mixture was cooled to room temperature and filtered through celite, then concentrated in vacuo to give the crude product. The crude product was used in the next step without further purification.

Reaction scheme 2, stage 4. To a stirred suspension of dichloropyrimidine (1 equiv.) in 1,4-dioxane (90 vol.) was added boronic ester (1.0 equiv.) and RD(RRIZ3)4 (0.03 equiv. ). A 2 M solution of K2SOZ (3 eq.) was added to the resulting mixture and heated at a temperature of 90 "C for 16 h in an M2 atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in a mixture of EtOAc:water (1:11 ) (100 ppm), and the resulting solution was filtered through celite, the organic layer was separated, and then the aqueous layer was extracted

From EUAs (50 06). The combined organic layers were washed with saturated aqueous Mass (20 vol.), dried over Na 2 O 4 , filtered, and the solvent was removed in vacuo. The obtained residue was purified by flash column chromatography (eluent: 13:1 | EIAs:heptane) to obtain the desired target compound.

Reaction scheme 2, step 5. 4-Chloro-6-substituted-phenyl-pyrimidine (1 equiv), RasCIg(arr) OsCM (0.05 equiv) and triethylamine (2 equiv) were suspended in degassed MeOH (50 vol .) in a bomb equipped with a magnetic stirrer. The atmosphere in the reaction vessel was replaced by M2 by sequential vacuuming and injection of M2 gas (this process was repeated three times). The bomb was then purged with CO by sequential CO injection and vacuuming. The vessel was pressurized to 5 bar CO, and the vessel was heated at 50 °C with stirring for 16 h. The reaction vessel was allowed to cool to room temperature before being purged with CO and charged with M2. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (30 vol.) and water (30 vol.). The organic layer was separated, washed with saturated aqueous MaCl (15 vol.), dried over Ma2504, filtered and concentrated under reduced pressure. Purification by recrystallization using

Meon led to the target compound.

Reaction scheme 2, step 6. 6-substituted-phenyl-pyrimidine-4-carboxylic acid methyl ester (1 equiv.) was suspended in TNE (20 vol.), 2 M Mahon (2.5 equiv.) and stirred at room temperature temperature for 4 hours. The solvent (TNE) was removed, and the reaction mixture was acidified with 2 M HCl. The resulting solid was filtered and washed with water to give the desired product.

The following compounds were prepared essentially as described above. mass spectrometry

MM

- on IM-AANI" - 293/295, 100 Fo 2 re 292.72 with retention time - 4.18 o o min.

SI her -i he IM-ANI" - 319, 100 95 pri

From che 318.76 retention time - 4.61 minutes.

SI

her

Y - on IM-ANI" - 307/309, 100 Fo 4 V 306.75 with retention time - 4.37 mass; about a minute.

SI

Her - he IM-ANI" - 307/309, 100 Fo "Ж 306.75 with a holding time of 4.37 minutes.

SI

Her and he IM-ANI" - 291/293, 100 95

And 290.71 with a retention time of 3.93 minutes. (at

Her - ON IM-ANI" - 305/307, 100 96 7 С 304.79 with a holding time of 4.20 minutes.

SI and - on IM-MaH - 303/305, 100 95 302.72 with the retention time - 4.14 huo o min.

SI

5

Example C

Scheme of the reaction Z

I - Z o hesyussoyesyuesyuesoessuyusoyech ih sh y ek Cash p you a Stage: 70700700 btadn? From the

Staliya Z sht Uy chu" in m'v m'v more Sha po i I still more di and viya S

Reaction Scheme 3, Step 1. Triethylamine (19.01 mL, 146.92 mmol) was added dropwise to a solution of diethyl but-2-indioate (25.0 g, 146.92 mmol) and formamidine hydrochloride (11.83 g, 146.92 mmol) in acetonitrile (500 mL). The obtained red solution was heated at a temperature of 80 °C for 2.5 hours. After this time, the reaction mixture was cooled to a temperature of 5 °C using a saturated MaSi/ice bath, and the reaction mixture was stirred at this temperature for 25 minutes. At the end of this time, the obtained solid precipitate was collected by suction and dried on a slag funnel for 30 minutes in a vacuum at room temperature, after which it was dried in a vacuum at room temperature for 3 hours to obtain the target compound (21.3 g, yield 86 95) as a pale brown solid. Here we are. - 0.85 minutes. (method 3.5 minutes) t/72 (Ebu) (MANI 169.

Reaction Scheme 3, Step 2. Ethyl β-hydroxypyrimidine-4-carboxylate (21.3 g, 126.67 mmol) was dissolved in dry 100 mL of 2-necked flask. The flask was purged with a stream of nitrogen while cooling in an ice bath for 10 minutes. After this time, thionyl chloride (15.6 mL, 215.6 mmol) was added dropwise over 20 minutes, after which the reaction mixture was heated to room temperature and stirred under a nitrogen atmosphere for 2 hours. At the end of this time, the reaction mixture was carefully poured into 100 ml of ice water. They added

TVME (100 ml), the organic layer was separated, and the aqueous layer was extracted with an additional amount of TVME (3x100 ml). The combined organic layers were successively washed with water (2 x 100 ml) and brine (100 ml), then dried (М95О054), filtered and concentrated to give the target compound (8.8 g, yield 37 95) as a light yellow-hot powder . bH (500 MHz, OM5O) 9.23 (d (doublet), U-0.95 Hz, 1 H), 8.16 (d, 9U-1.10 Hz, 1 H), 4.39 (k ( quadruplet), 9-7.09 Hu, 2 H), 1.34 (t (triplet), uU-7.17 Hz, Z H). Here we are. - 1.43 minutes. (method 3.5 minutes) t/7 (Eb-) (MANI 187.

Reaction scheme 3, stage 3. Tripotassium phosphate (1.12 g, 5.63 mmol) was added as one

From a portion to a stirred solution of dioxaborolane (3.75 mmol) and ethyl b-chloropyrimidine-4-carboxylate (0.7 g, 3.75 mmol) in OME (20 mL). The mixture was degassed with nitrogen for 5 minutes, after which Ra(drpO2CI2 (0.14 g, 0.19 mmol) was added in one portion, then the mixture was heated to a temperature of 80 "C and stirred at the specified temperature for 16 hours in a nitrogen atmosphere. at the end of this time, the reaction mixture was cooled to room temperature and partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, washed successively with water (100 mL), then brine (100 mL), and then dried (Mo9504) , filtered and concentrated.The resulting brown solid was purified by flash column chromatography (elution: 40 95 EOAc, 60 95 heptane) to give the target compound.

Reaction scheme C, stage 4. Mahon (2 M solution, 0.63 ml, 1.27 mmol), and the mixture was stirred at room temperature for 16 hours, after which it was heated in a reflux flask for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, and the resulting precipitate was collected by filtration, washed with TNE (20 ml), and then dried in a vacuum to obtain the target compound.

The following compounds were prepared essentially as described above. mass spectrometry

If db on IM-ANI - 279/281, 100 Fo 278.04 with retention time - 3.65 yd/o per minute.

SI

Example 4

Reaction scheme 4

U y od y re y va o : ve vanssya PI o nos t nyu s U i Also y: -d

Y 50 Stage y 4 Stage 2 g Stage 3 OT Vi

Steel 415 has a steel

And shk and zu in. WITH

Reaction scheme 4, stage 1. Methylmagnesium bromide (1.4 M in toluene/TNE, 1.5 mL, 0.046 mol), and the mixture was stirred at this temperature under a nitrogen atmosphere for 1 hour. At the end of this time, the reaction mixture was allowed to warm to room temperature for 1 hour, after which it was stirred for another 1.5 hours. The reaction mixture was then cooled to 5 °C in an ice bath and stirred for 10 minutes, after which saturated ammonium chloride (40 mL) was added dropwise and stirring was continued at this temperature for another 10 minutes, and then the reaction mixture was allowed to warm to room temperature . Then the resulting mixture was extracted with ethyl acetate (1x100 ml), the organic layer was successively washed with water (100 ml) and saline solution (100 ml), after which it was dried (M9504), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 10 9o ethyl acetate, 90 95 heptane) to give the target compound (4.33 g, yield 81 95) as a colorless oil. bH (500 MHz, ЮМ5О) 7.64 (d, 9U-1.58 Hz, 1 H) 7.49-7.60 (m (multiplet), 2 H) 5.47 (d, 9U-3.00 Hz, 1 H) 4.96 (dd (double doublet), y-6.07, 2, 60 Hz, 1 H) 1.28 (d, 9-6.31 Gu, Z H).

Reaction scheme 4, stage 2. To a cooled (0 "C) stirred solution of 1-(4-bromo-2-chlorophenyl)ethan-1-ol (1.5 g, 6.4 mmol) in OME (15 mL) for Sodium hydride (60 95 in oil, 0.38 g, 9.6 mmol) was added in portions over 5 minutes, and the reaction mixture was stirred at this

From the temperature for 20 minutes in a nitrogen atmosphere. At the end of this time, methyl iodide (0.48 mL, 7.6 mmol) was added in one portion, and the reaction mixture was allowed to warm to room temperature, after which the reaction mixture was stirred for another 18 hours. The reaction was quenched by adding water dropwise (15 ml) for 10 minutes, and the resulting solution was extracted with ethyl acetate (2x30 ml). The combined organic extracts were washed sequentially with water (100 mL) and brine (10 mL), then dried (M95054), filtered and concentrated to give the target compound (1.5 g, yield 99 95) as a yellow oil. bH (500 MHz, OM5O) 7.71 (d, 9U-1.89 Gu, 1 H) 7.60 (dd, U-8.35, 1.89 Hz, 1 H) 7.39 (d, 9 -8.35 Hz, 1 H) 4.63 (k, U-6.46 Hz, 1 H) 3.16 (s (singlet), C H) 1.26-1.38 (m, C H) .

Reaction scheme 4, steps 3, 4 and 5 were carried out as described for reaction scheme 3.

The following compounds were prepared essentially as described above. mass spectrometry

IF

- he IM-AANI" - 293/295, 100 Fo 10 292.72 with the retention time - 3.72 Ido per minute.

SI

Example 5

The following compounds can be prepared as essentially described above.

Chemical structure

her

N

14 4 o 6-(3-chloro-4-(cyclopropoxymethyl)- o o phenyl)pyrimidine-4-carboxylic acid

SI

her

N

12 4 o 6-(3-chloro-4-(1-cyclopropoxyethyl)- o o phenyl)pyrimidine-4-carboxylic acid

SI mm - on 13 o 6-(4-chloro-3-cyclopropoxy-

He phenyl) pyrimidine-4-carboxylic acid. Y mm - on 14 o 6-(4-chloro-3-isopropoxy-

SI phenyl)pyrimidine-4-carboxylic acid in mm - on

Ge) 6-(4-chloro-3-isobutoxy-phenyl)pyrimidine-15 SI 4-carboxylic acid d

Example 6

Below is a generalized procedure for controlling the hydroxylation of I! -kynurenine (KUM) with the formation of the product 3-hydroxy-kynurenine (ZON-KUM) by the LC/MS method. The product was quantified by monitoring multiple reactions using MS.

Zo

Main reagents:

Compound: Initial concentrations: 10 mM in 100 95 OM5O

Cell line: CHO 517 NI5 CMO cell line, 1E4 cells/well/100 µl in a 96-well cell plate

Substrate: I-Kynurenine (Zidta: cat. Mo K3750, initial concentration: 10 mM in 100

MM potassium phosphate buffer, pH 7.4)

Analysis conditions:

Medium: OriiMet (I x medium with reduced serum content, zhi -glutamine i

STAINLESS STEEL - phenolic red; SIVSO: cat. Mo 11058)

Analysis volume: 200 μl

Tablet format: 9b-well tablet, transparent (Sogpipod)

Reading: product quantification (ZON-KUM) using product-specific MMR

Reading device: LC/MS/MS

Analysis protocol: - prepared serial dilutions (with a factor of 3) of the compound in 100,956 OM5O (upper concentration 6.67 mM, 100 95 OM50)

From points: 6.67 mm; 2.22 mm; 0.74 mm; 0.247 mm; 0.082 mm; 0.027 mm; 0.009 mm; 0.003 mm - a 300-fold concentrated solution of each concentration of the compound was prepared (upper concentration 22.22 µM, 0.3 96 OM5O) in the OriyaMet medium (22.2 µM; 7.41 µM; 2.47 µM; 0.82 µM; 0.27 μM; 0.09 μM; 0.03 μM; 0.01 μM - substrate (10 mM) was prepared at a concentration of 1.1 mM in the medium - the medium was taken from the cell plate - the cells were washed with OriMet (100 μl/well ) and the medium was taken again - a mixture for analysis: 90 μl of OriMet/well and 90 μl of the compound/well in each concentration

The final upper concentration of the compound: 10 µM; 0.15 95 OM5OYI

The final lower concentration of the compound: 0.004 µM; 0.15 95 OM5O) - preliminary incubation: 30 minutes. at a temperature of 37 "С - 20 μl/well of a 1.1 mM substrate solution was added (final concentration in the assay: 100 μM) - positive control: 200 μl OriiMet - negative control: 180 μl OriiMet20 μl of 1.1 mM substrate - incubated "24 h. at a temperature of 37 "C - transferred 100 μl from each well into a transparent 96-well plate (Sogpipo) - added 100 μl/well of 10 95 trichloroacetic acid (TCA) in water - centrifuged the plate for 3 minutes. at 4000 rpm. - the product was detected by the LC/MS method (injection of 50 μl/well; 2.5-fold overflow of the sampling loop with a volume of 20 μl)

Data analysis: ISvo was calculated using an automated selection algorithm (Azh

Analysis)

Example 7

Below is described a method of controlling the hydroxylation of I-kynurenine (KIM) for obtaining

From the product of 3-hydroxy-kynurenine (ZON-KUM) by the LC/MS method. The product was quantified using multiple reaction monitoring.

Main reagents:

Compound: Initial concentrations: 10 mM in 100 95 OM5BO

Enzyme: KMO enzyme obtained in Emoies by isolating mitochondria from CHO-5T NI5 KMO cells

Substrate: I-Kynurenine (Zidta: cat. Me KZ3750)

Initial concentration: 10 mM in 100 mM potassium phosphate buffer, pH 7.4

Analysis conditions:

Buffer: 100 mM potassium phosphate, pH 7.4, 200 μm MAORN, 0.4 U/ml C6P-YUN (glucose-6-phosphate dehydrogenase), 3 mm ObR (O-glucose-6b-phosphate)

Analysis volume: 40 μl

Plate format: 384-well plate, transparent (Maigih)

Reading: product quantification (ZON-KUM) using product-specific MMR (multiple reaction monitoring)

Reading device: LC/MS/MS

Analysis protocol: - prepared serial dilutions (with a factor of 3) of the compound in 100,906 OM5O (upper concentration

- 10 mm, 100 95 UOM50)

From points: 10 mm; 3.33 mm; 1.11 mm; 0.37 mm; 0.12 mm; 0.04 mm; 0.0137 mm; 0.0045 mm, 0.0015

MM

- a 3.33-fold concentrated solution of each concentration of the compound was prepared (upper concentration 300 μM, C 95 OM5O) in the buffer for analysis

Concentrations: 300 µM; 100 µM; 33.3 μM; 11.1 µM; 3.70 µM; 1.23 µM; 0.41 µM; 0.137

MKM

- a substrate (10 mM) was prepared at a concentration of 1 mM in a buffer for analysis - a buffer for analysis; 4 μl of compound/well of each concentration - 24 μl of assay buffer/well - 8 μl of human CMO enzyme "4 μl of 1 mM substrate (final concentration - 100 μm)

The final upper concentration of the compound: 30 µM; 0.3 95 OM5O)

The final lower concentration of the compound: 0.0137 µM; 0.3 95 OM5O) - positive control: 4 μl of 50 μM ЕСЕ28833 in analysis buffer (0.5 96 OM5O)1 (final concentration in the analysis - 5 μM) and 24 μl of analysis buffer/well - 8 μl of human CMO enzyme i 4 µl of 1 mM substrate (final concentration - 100 µM) - negative control: 28 µl of buffer for analysis/well i - 8 µl of human CMO enzyme "« 4 µl of 1 mM substrate (final concentration - 100 µM) - incubated for 400 minutes. at RT - 40 μL/well of 10 O trichloroacetic acid in water was added to stop the assay and protein precipitation - centrifuge the plate for 3 min at 4000 rpm - detect the product by LC/MS (injection of 50 μL /well; 2.5-fold overflow of the sampling loop with a volume of 20 μl)

Data analysis: ISvo was calculated using an automated selection algorithm (Azh

Analysis).

Example 8

The method of controlling the hydroxylation of I-kynurenine (KUM) with the production of 3-hydroxy-kynurenine (ZON-KUM) by the LC/MS method is described. The product was quantified using monitoring

From multiple reactions (MMP method).

Main reagents:

Compound: Initial concentrations: 10 mM in 100 95 OM5O

Enzyme: CMO enzyme obtained by Emoies from mouse liver (aged 4-6 weeks) by mitochondrial isolation as described in the literature

Substrate: I-kynurenine (5idta: cat. Mo KZ3750, initial concentration: 10 mM in 100 mM potassium phosphate buffer, pH 7.4)

Analysis conditions:

Buffer: 100 mM potassium phosphate, pH 7.4, 200 μm MAORN, 0.4 U/ml О6Р-ЮН (glucose-6-phosphate dehydrogenase), 3 mm ОР (О-glucose-6b-phosphate)

Analysis volume: 40 μl

Plate format: 384-well plate, transparent (Maigih)

Reading: product quantification (ZON-KUM) using product-specific MMR

Reading device: LC/MS/MS

Analysis protocol: - prepared serial dilutions (with a factor of 3) of compounds in 100 956 OM5O (upper concentration - 10 mM, 100 95 ЮОМ50)

From points: 10 mm; 3.33 mm; 1.11 mm; 0.37 mm; 0.12 mm; 0.04 mm; 0.0137 mm; 0.0045 mM, 0.0015

MM

- a 3.33-fold concentrated solution of each concentration of the compound was prepared (upper concentration 300 μM, C 95 OM5O) in the buffer for analysis

Concentrations: 300 µM; 100 µM; 33.3 μM; 11.1 µM; 3.70 µM; 1.23 µM; 0.41 µM; 0.137

MKM

- a substrate (10 mM) was prepared at a concentration of 1 mM in a buffer for analysis - a buffer for analysis; 4 μl of compound/well of each concentration - 24 μl of assay buffer/well - 8 μl of mouse CMO enzyme -- 4 μl of 1 mM substrate (final concentration - 100

MKM)

The final upper concentration of the compound: 30 µM; 0.3 95 OM5O)

The final lower concentration of the compound: 0.0137 µM; 0.3 95 OM5O) - positive control: 4 μl of 50 μM ЕСЕ28833 in the analysis buffer, 0.5 96 ЮОМ5О final concentration in the analysis - 5 μM | 24 μl of buffer for analysis/well i- 8 μl of mouse CMO enzyme t 4 μl of 1 mM substrate (final concentration - 100 μM - negative control: 28 μl of buffer for analysis/well - 8 μl of mouse CMO enzyme "4 μl of 1 mM substrate (final concentration - 100 μM - incubated for 40 min. at room temperature - added 40 μl/well of 10 96 trichloroacetic acid in water to stop the analysis and protein precipitation - centrifuged the tablet for 3 min. at 4000 rpm. - the product was detected by LC/MS (injection of 20 μl/well, 2-fold overflow of the sampling loop with a volume of 10 μl)

Data analysis: ISvo was calculated using an automated selection algorithm (Azh

Analysis).

Example 9

Using procedures similar to those described in this application, the activity of the following compounds was analyzed. of pure and applied chemistry) acid " carboxylic acid 6-(3-chloro-4-(cyclopentyloxy)-phenyl)-pyrimidine-4- carboxylic acid (5)-6-(4-second-butoxy-3-chloro-phenyl) -pyrimidine-4-carboxylic acid (8)-6-(4-tert-butoxy-3-chloro-phenyl)-pyrimidine-4-carboxylic acid carboxylic acid carboxylic acid 6-(33-chloro-4-(cyclopropylmethoxy)- phenyl)pyrimidine-4-carboxylic acid 6-(4-chloro-3-fluoro-phenyl)pyrimidine-4-carboxylic acid

Example 10

Microdialysis procedure for mouse studies

Animals were anesthetized using isoflurane (2,905, 800 ml/min. 02). Bupivacaine/epinephrine was used for local anesthesia, finadine or carprofen was used for pre-/postoperative analgesia. Animals were placed in a stereotaxic frame (Corey Ipsygytepev, USA). I-shaped probes were inserted into the striatum (membrane: polyacrylonitrile, impact surface 3 mm; VgaipipK, the Netherlands). After the surgical procedure, the animals were kept in cages one at a time; animals received food and water without restriction.

Experiments were performed one day after the surgical procedure. On the day of the experiment, the probes of the animals were connected with a flexible REEK tube to a microperfusion pump (syringe pump

Nagmaga RNO 2000, Noyivyup, MA or similar). I-shaped probes for microdialysis were perfused with CSF (artificial cerebrospinal fluid) containing 147 mM Mac, 3.0 mM KCl, 1.2 mM CaCl2, and 12 mM MacCl2 at a flow rate of 1.5 μl/min. Samples for microdialysis were collected at 20-minute intervals using an automatic fraction collector (820 Misgozatrieg,

Opimepiog, MA or similar) in minirlacones containing 10 μl each of 0.02 M formic acid (REA) and 0.04 95 ascorbic acid in ultrapurified H2O. At the moment of time it is -30 minutes. vehicle or CMO inhibitor was administered to confirm central and peripheral CMO inhibition at the time of kynurenine administration. At time point 1-0, vehicle or kynurenine was administered. Microdialysate samples were taken within 240 minutes. after kynurenine administration. All samples after dialysis were stored at a temperature of -80 "C before analysis. The levels of any or all PC metabolites - KUM, KUMA, 3-OH-KUM, AA and OA - in the dialysates were quantitatively determined by the method

РХ-MS/MS with the involvement of Vgaiip5 Op-Hype company. After the experiment, the mice were killed, and samples of the terminal region of the brain (striatum and cortex), liver, kidneys,

plasma and CMP were selected for PC metabolite analysis. Levels of PC metabolites were measured in samples of the terminal region of the brain (striatum and cortex), liver, kidneys, plasma, and SMP with the involvement of Vgaip5 Op-IGipe company. Finally, the levels of kynurenine and KMO inhibitors in the samples of the dosage formulations were quantitatively determined with the involvement of the Vgaip5 Op-I ipe company.

Example 11

The method of studying the modulation of KUM, KUMA, AA and 3-NK by means of inhibition is revealed

KMO Compound b in the extracellular space of the striatum. More specifically, the purpose of this experiment was to demonstrate dose-dependent differences in the increase in the level of central PC metabolites (KUM, KUMA, AA, 3-NK) when different levels of Compound 6 were administered in the animal's brain. After the microdialysis procedure described in this application, the levels of PC metabolites - CUM,

KUMA, 3-NK and AA - in the dialysate were quantitatively determined by the LC-MS/MS method with the involvement of the company

Vgaipz Op-Y ipe.

Microdialysis was performed after p.o. (oral) administration of Compound 6 at different dose levels (3 mg/kg, 10 mg/kg or 30 mg/kg). Compound 6 was shown to cause a dose-dependent increase in the levels of CUM (see Fig. 1), as well as the protective metabolites of CUM (see Fig. 2) and AA (see Fig. 3) in the mouse striatum, while relatively metabolite 3-NK had little or no effect (see Fig. 4).

Example 12

A method of studying the modulation of the level of PC metabolites in HO animals similar to DT (wild-type) controls has been revealed. More specifically, the purpose of this experiment was to demonstrate that Compound 6 modulates differences in increasing the level of KUMA in the animal's brain.

After the microdialysis procedure described in this application, the levels of the PC KUMA metabolite in the dialysate were quantitatively determined by the LC-MS/MS method with the involvement of the Vgaip5 Opipe company.

Microdialysis was performed after p.o. administration of Compound b in a concentration of 3 mg/kg or 10 mg/kg.

Compound 6 was shown to increase KUMA in both DT animals (see Fig. 5 ) and HO animals (see Fig.

Fig. 6), and the difference between these two groups was insignificant.

Example 13

A method of studying the pharmacodynamic effects of kynurenine (30 mg/kg, p.o.) and Compound 6 (30 mg/kg, p.o.), which were administered simultaneously or independently, on the extracellular levels of KUM, KUMA,

From 3-ON-KUM, AA and OA in the striatum (STC) of adult male DT mice. More specifically, the purpose of this experiment was to demonstrate differences in the increase in the level of the central PC metabolite when kynurenine is administered compared with the administration of a CMO inhibitor, which is expected to block kynurenine catabolism at a post-CMO stage in the brain of the animal.

After performing microdialysis after p.o. administration of the compound (30 mg/kg, p.o.) was carried out with the simultaneous administration of Compound 6 (30 mg/kg, p.o.) or kynurenine and Compound 6 (30 mg/kg, each p.o.).

Compound 6 was shown to increase CUM (see Fig. 7) as well as protective metabolites of CUM (see Fig.

Fig. 8) and AA (see Fig. 9) in the striatum of mice, while kynurenine alone had little or no effect on these metabolites. Moreover, p.o. the introduction of Compound 6 blocks the toxic metabolites 3-OH-KUM (see Fig. 10) and OA (see Fig. 11), while the introduction of kynurenine increases the level of these metabolites in connection with the catabolism of kynurenine in the mouse brain.

Although some embodiments of the present invention have been shown and described, various modifications and substitutions are possible within the spirit and scope of the present invention. For example, when interpreting the claims, it is not intended that the claims set forth below should be interpreted in any more narrow way than is literally defined by the said claims, and thus, it is not intended that the examples of implementation options from the description of the invention should be included in the formula of the invention. Accordingly, it should be understood that this invention has been described by way of illustration and not to limit the scope of the claims.

Claims (10)

FORMULA OF THE INVENTION 1. A compound of the Formula: tv fruits i z songoi i aio or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of an HIV-related disorder in an HIV-infected subject together with an antiviral agent. 2. The compound according to claim 1, where said medicinal product is a co-packaged medicinal product containing an antiviral agent and said compound or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, where the indicated antiviral agent is selected from entry inhibitors, fusion inhibitors, glycosidase inhibitors, CSK5 antagonists, immune-based therapy options, integrase inhibitors, maturation inhibitors, combinations of drugs of different classes, non-nucleoside reverse transcriptase inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, pharmacokinetic enhancers and protease inhibitors. 4. The compound according to claim 1 or 2, where the specified antiviral agent is selected from nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, CSK5 antagonists and integrase chain transfer inhibitors, as well as combinations of the specified agents. 5. The compound according to claim 1 or 2, where the indicated antiviral agent is selected from the group that includes drugs: amdoxovir, Aptivus?, Aralen?, Atripla?, senecriviroc, Cobicistat", Combivire-, Complera?, Krixivan", DermavVirU, Edurant" , elvitegravir? RAVO 140, Rescriptor?U, Retrovir?U, ReatazU, 58-728-І, Selzentry?, 5РИ-452, Stribild?, Sustiva?, tenofovir alafenamide fumarate, Tivicay?, Trii", Trizivir-U, Truvadag, Videx- , Videx? ES, Viracept", Viramune-, Viramune HE, Viread", Zerit? and Ziagen?, as well as combinations of the mentioned means. 6. The compound according to claim 1 or 2, where the specified antiviral agent is an antiviral agent, which is a highly active antiretroviral therapy. 7. The compound according to any one of claims 1-6, where HIV is HIV-1. 8. The compound according to claim 7, where HIV-1 is HIV-1 of group M. 9. The compound of any one of claims 1-8, wherein the disorder associated with HIV is a neurological disorder. 10. The compound of claim 9, wherein the neurological disorder is selected from the group consisting of AIDS-dementia, AIDS-induced encephalopathy, HIV-associated neurocognitive disorder, asymptomatic neurocognitive impairment, moderate neurocognitive disorder, moderate cognitive movement disorder, vacuolar myelopathy, peripheral neuropathy, and polymyositis.